記述言語：英語   掲載種別：研究論文（学術雑誌）  

PURPOSE: Although several potential radioprotectants have been explored, radiation esophagitis is still difficult to control. Further development of supportive therapies is required. Our purpose was to investigate the efficacy and safety of cystine and theanine for esophagitis in non-small cell lung cancer (NSCLC) patients undergoing chemoradiotherapy (CRT). METHODS: This study is a prospective observational study. The participants were recruited from unresectable locally advanced NSCLC who had scheduled to receive weekly paclitaxel or nab-paclitaxel/carboplatin plus radiation therapy (60 Gy in 30 fractions) for 6 weeks. They took an oral amino acid supplement containing 700 mg cystine and 280 mg theanine once daily regardless of CRT timing from the start of CRT until completion. The primary endpoint was the incidence of any grade esophagitis. The secondary endpoints were quality of life (QoL) and adverse events (AEs). RESULTS: A total of 26 patients were evaluated. All participants completed 60 Gy of RT in 30 fractions. The overall incidence of esophagitis was 73%; however, no ≥ grade 3 was reported. There were no AEs likely to be related to cystine and theanine. The mean EuroQoL 5-Dimension 5-Level health index score before and after chemoradiotherapy was 0.952 ± 0.0591 and 0.952 ± 0.0515 (P = 0.89), and the mean Visual Analogue Scale scores before and after treatment were 67.9 ± 15.4 and 79.4 ± 13.2 (P = 0.0047), respectively. CONCLUSION: Our study showed no severe esophagitis, any AEs, nor QoL decrease in NSCLC patients receiving CRT. Cystine and theanine are potentially effective to reduce severe CRT-induced esophagitis. TRIAL REGISTRATION: UMIN000052622, 26 October 2023, retrospectively registered.

DOI： 10.1007/s00520-024-08613-0

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記述言語：日本語   出版者・発行元：(一社)日本医療薬学会  

院外処方における処方禁忌チェックシステムと院外処方箋における検査値印字による2段階チェックの有用性について評価した。処方禁忌チェックは2018年8月から稼働し、その17ヵ月後の2020年1月から院外処方箋への検査値印字を開始したことを踏まえ、17ヵ月間を1期間として対象期間を設定した。各調査期間における禁忌アラート該当件数は第1期が9850件(3.62%)、第2期が9464件(3.29%)、第3期が9460件(3.41%)、第4期が9823件(3.34%)であり、第1期に比べて第2、3、4期の割合はいずれも有意に低下した。検査値関連の疑義照会による処方変更件数は第2期が5件、第3期が66件、第4期が47件であり、第2期に比べて第3期と第4期で検査値関連の疑義照会による処方変更件数は約10倍に増えており、割合としても有意に増加した。院外処方箋に検査値印字を行う2段階チェックは医薬品の適正使用の推進に有用であることが示された。

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier BV  

Everolimus is used for immunosuppression after renal transplantation. This study aimed to develop a population pharmacokinetic (PopPK) model of everolimus using therapeutic drug monitoring (TDM) data of patients under long-term multiple immunosuppressive therapy, including tacrolimus. To develop the model, 185 renal transplant recipients with 3358 everolimus blood concentrations during a median postoperative period of 35.3 months were included. The PopPK model is described as a one-compartment model with first-order absorption. The population mean of apparent clearance is 8.92 L/h (relative standard error = 3.6%), and this negatively correlated with the dose-normalized concentration (C/D) of tacrolimus and hematocrit value, and positively correlated with a daily dose of everolimus (i.e. TDM effect). The usefulness of dose adjustment using the final popPK model was assessed by a simulation study. The ratio of the first trough measurement within the therapeutic range of 3-8 ng/mL increased from 69.8% in the original dose to 87.9% in the individual dose calculated by the final PopPK model. The tacrolimus C/D ratio before initiating everolimus therapy and the hematocrit value were useful to estimate the initial dose of everolimus and can improve the safety and effectiveness of immunosuppressive therapy involving everolimus.

DOI： 10.1016/j.dmpk.2024.101009

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Osimertinib is used as the first-line therapy for patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, early dose reduction is often required due to adverse events (AEs). This study aimed to evaluate the effect of early dose reduction of osimertinib on efficacy and safety. This was a retrospective study including patients with EGFR-mutated NSCLC who were started on osimertinib as the first-line therapy between August 2018 and December 2021. Patients whose doses were reduced to less than 80 mg/day within 6 months of osimertinib initiation or started at 40 mg/day were defined as the dose reduction group. The primary endpoint was progression-free survival (PFS). Factors affecting PFS were explored using the Cox proportional hazards model. A total of 85 patients were included in this study. No significant differences in patient characteristics were observed between the dose reduction (n = 25) and standard dose groups (n = 60). The median PFS in the dose reduction group was significantly prolonged compared with that in the standard dose group (26.0 months vs. 12.0 months, p = 0.03). Multivariable analysis of 84 patients, excluding a patient with unknown brain metastasis, revealed that EGFR exon 21 L858R mutation, malignant pleural effusion or pleural metastasis, liver metastasis, and dose reduction within 6 months were independent factors affecting PFS. Early dose reduction of osimertinib is an effective therapeutic strategy for prolonging PFS in patients with EGFR-mutated NSCLC.

DOI： 10.1007/s10637-024-01432-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Brexpiprazole is a second-generation antipsychotic approved in Japan in 2018; however, information on placental passage and breast milk transfer remains limited. In this report, the patient, a 30-year-old pregnant woman with schizophrenia, was medicated with brexpiprazole, risperidone, and quetiapine. METHODS: The study used high-performance liquid chromatography-tandem mass spectrometry to determine the concentrations of brexpiprazole, quetiapine, risperidone, and its active metabolite (paliperidone) in maternal and neonatal plasma, cord venous plasma, and breast milk. Maternal plasma samples were obtained approximately 2 and 8 hours after the last administration of antipsychotics on the day of delivery and at the estimated drugs' trough time on days 1, 3, and 5 after delivery. RESULTS: The maternal plasma concentrations of brexpiprazole, quetiapine, and paliperidone increased by approximately 3.5-fold on the fifth day compared with those on the day of delivery, whereas the risperidone concentration remained almost constant. Moreover, the neonatal plasma concentrations of the 4 drugs immediately after birth were indistinguishable from the umbilical cord concentrations and gradually decreased, except for risperidone. Relative infant doses of these compounds were below 1.1%. CONCLUSIONS: Pregnancy status notably alters the pharmacokinetic properties of antipsychotics. Therefore, close and careful monitoring of clinical symptoms should be considered during pregnancy and after delivery. Although brexpiprazole is transferred to neonates through the placenta, breastfeeding is still possible because the relative infant dose value of this drug was much less than 10%.

DOI： 10.1097/FTD.0000000000001197

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記述言語：日本語   出版者・発行元：(一社)日本病院薬剤師会  

一包化錠剤仕分け装置の運用過程でテルミサルタン錠の変色を経験した。まず,テルミサルタン錠とドパミン誘導体を含む錠剤(レボドパ/カルビドパ錠,ドロキシドパ錠または粉砕したメチルドパ錠)との接触実験を行ったところ着色を確認した。一方で,テルミサルタンとドパミン誘導体が構造的に化学反応する可能性は低いため,テルミサルタン錠の添加剤であるメグルミンに着目し,メチルドパと混合下で基礎的検討を行った。水分存在下では着色が加速し,着色成分の質量分析を行った結果,複数のメチルドパ分解産物の生成が示された。すなわちドパミン誘導体は水分存在下でメグルミンと接触することで酸化的に分解され,さらに重合することでメラニン類似物質となり,それがテルミサルタン錠の変色原因であることが示唆された。以上,添加剤としてメグルミンを含有する薬剤では,無包装下でドパミン誘導体との接触による製剤学的相互作用に注意を要する。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2024&ichushi_jid=J04451&link_issn=&doc_id=20240411310006&doc_link_id=%2Fdg4hppha%2F2024%2F006004%2F006%2F0395-0401%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2024%2F006004%2F006%2F0395-0401%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Rituximab, an anti-CD20 monoclonal antibody, can cause infusion reactions (IRs), especially during the initial rituximab infusion therapy. Generally, patients are administered a histamine H1-receptor antagonist before the rituximab infusion, along with an antipyretic analgesic, to prevent or reduce IRs. Multiple retrospective case-control studies indicate that the second generation of histamine H1-receptor antagonists might be more effective than the first generation in suppressing IRs caused by the rituximab infusion. OBJECTIVE: This study aimed to assess the efficacy of first- and second-generation histamine H1-receptor antagonists for preventing IRs resulting from the initial infusion of rituximab in patients diagnosed with non-Hodgkin lymphoma. METHODS: This is a phase II, double-blind, active-controlled randomized trial. It will be a multicenter study conducted across 3 facilities that aims to enroll a total of 40 patients diagnosed with non-Hodgkin lymphoma who will receive their initial rituximab infusion. Participating patients will be administered hydroxyzine pamoate or bepotastine besilate, representing first- or second-generation histamine H1-receptor antagonists, respectively. This will be combined with 400-mg acetaminophen tablets taken approximately 30 minutes before the first infusion of rituximab. The primary end point of this trial is to assess severe IRs, equivalent to grade 2 or higher as defined by the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0, that occur within a 4-hour period after the initiation of rituximab infusion. The secondary end points include assessing the severity of the initial IR, the maximum severity of the IR, and the duration between rituximab infusion initiation and the onset of the first IR within a 4-hour period. Additionally, the trial will evaluate histamine H1-receptor antagonist-induced drowsiness using the visual analogue scale, with each patient providing their individual response. RESULTS: This study began with patient recruitment in April 2023, with 17 participants enrolled as of November 12, 2023. The anticipated study completion is set for February 2026. CONCLUSIONS: This study is the first randomized controlled trial comparing the effects of oral first- and second-generation histamine H1-receptor antagonists in preventing IRs induced by the initial administration of rituximab. The findings from this study hold the potential to establish the rationale for a phase III study aimed at determining the standard premedication protocol for rituximab infusion. TRIAL REGISTRATION: Japan Registry of Clinical Trials jRCTs051220169; https://jrct.niph.go.jp/latest-detail/jRCTs051220169. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/54882.

DOI： 10.2196/54882

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記述言語：日本語   出版者・発行元：(一社)日本医療薬学会  

退院時薬剤情報提供が入院中に中止した潜在的不適切処方(PIMs)の中止維持に有用であるかについて検討するため、入院中にPIMsを中止して退院した65歳以上の循環器内科・心臓血管外科病棟患者について後方視的調査を行った。その結果、お薬手帳を用いた退院時薬剤情報提供を実施した群におけるPIMsの中止維持薬剤割合は86.1%と高く、薬剤情報提供が個別のPIMsの中止維持に有効であることが示唆された。PIMsの再開と関連する因子として中止維持の評価時点が再入院時であることが特定され、お薬手帳を介して退院時薬剤情報が共有されないまま他院へ通院することがPIMs再開のリスクとなることが示唆された。退院時の薬剤情報提供は、診療情報が共有されない他院への通院患者において一般的に回避すべきPIMsの中止維持に有効であり、より安全で一貫性のある薬物治療の提供に貢献できると考えられた。

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記述言語：英語  

DOI： 10.1007/s10157-023-02436-9

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担当区分：筆頭著者,　責任著者   記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(公社)日本薬学会  

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2023&ichushi_jid=J01459&link_issn=&doc_id=20231109320005&doc_link_id=%2Fcs7yakug%2F2023%2F014311%2F005%2F0911-0916%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fcs7yakug%2F2023%2F014311%2F005%2F0911-0916%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1007/s10157-023-02415-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The prevalence of CKD may be higher in patients with cancer than in those without due to the addition of cancer-specific risk factors to those already present for CKD. In this review, we describe the evaluation of kidney function in patients undergoing anticancer drug therapy. When anticancer drug therapy is administered, kidney function is evaluated to (1) set the dose of renally excretable drugs, (2) detect kidney disease associated with the cancer and its treatment, and (3) obtain baseline values for long-term monitoring. Owing to some requirements for use in clinical practice, a GFR estimation method such as the Cockcroft-Gault, MDRD, CKD-EPI, and the Japanese Society of Nephrology's GFR estimation formula has been developed that is simple, inexpensive, and provides rapid results. However, an important clinical question is whether they can be used as a method of GFR evaluation in patients with cancer. When designing a drug dosing regimen in consideration of kidney function, it is important to make a comprehensive judgment, recognizing that there are limitations regardless of which estimation formula is used or if GFR is directly measured. Although CTCAEs are commonly used as criteria for evaluating kidney disease-related adverse events that occur during anticancer drug therapy, a specialized approach using KDIGO criteria or other criteria is required when nephrologists intervene in treatment. Each drug is associated with the different disorders related to the kidney. And various risk factors for kidney disease associated with each anticancer drug therapy.

DOI： 10.1007/s10147-023-02372-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

This comprehensive review discusses the dosing strategies of cancer treatment drugs for patients with impaired kidney function, specifically those with chronic kidney disease (CKD), undergoing hemodialysis, and kidney transplant recipients. CKD patients often necessitate dose adjustments of chemotherapeutic agents, e.g., platinum preparations, pyrimidine fluoride antimetabolites, antifolate agents, molecularly targeted agents, and bone-modifying agents, to prevent drug accumulation and toxicity due to diminished renal clearance of the administered drugs and their metabolites. In hemodialysis patients, factors such as drug removal from hemodialysis and altered pharmacokinetics demand careful optimization of anticancer drug therapy, including dose adjustment and timing of administration. While free cisplatin is removed by hemodialysis, most of the tissue- and protein-bound cisplatin remains in the body and rebound cisplatin elevations are observed after hemodialysis. It is not recommended hemodialysis for drug removal, regardless of timing. Kidney transplant patients encounter unique challenges in cancer treatment, as maintaining the balance between reduction of immunosuppression, switching to mTOR inhibitors, and considering potential drug interactions with chemotherapeutic agents and immunosuppressants are crucial for preventing graft rejection and achieving optimal oncologic outcomes. The review underscores the importance of personalized, patient-centric approaches to anticancer drug therapy in patients with impaired kidney function.

DOI： 10.1007/s10147-023-02377-z

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) inhibitors represent the standard of care for metastatic renal cell carcinoma (RCC). However, treatment outcomes are relatively poor, suggesting a potential problem with tolerating mTOR inhibitors. The aim of this study was to establish everolimus-resistant sublines and to compare their molecular characteristics with those of their counterparts. MATERIALS AND METHODS: Human-derived RCC, Caki-2, and 786-O cells were continuously exposed to everolimus at 1 μM, and the established resistant sublines were designated as Caki/EV and 786/EV, respectively. Cellular characteristics were compared between both cells. RESULTS: Caki/EV and 786/EV cells showed a decrease in sensitivity to everolimus as well as other mTOR inhibitors. Expression of mTOR and its effectors exhibited no alteration in resistant sublines and their counterparts. However, phosphorylation of S6K, an index of mTOR activity, decreased in resistant sublines. PCR array analysis of mTOR signaling pathway-related factors indicated that the expression of INSR, TP53, and IGFBP3 increased in Caki/EV cells, whereas that of TELO2, HRAS, and SGK1 was up-regulated in 786/EV cells. The levels of DDIT4, DEPTOR, HIF1A, and PLD1 mRNAs decreased in both cell lines. CONCLUSION: The novel everolimus-resistant Caki/EV and 786/EV cells exhibited cross-resistance to other mTOR inhibitors and decreased mTOR activity. Furthermore, down-regulation of DDIT4, DEPTOR, HIF1A, and PLD1 may contribute to everolimus resistance.

DOI： 10.21873/anticanres.16630

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担当区分：筆頭著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Optimised antithrombotic therapy requires clinical experience and an understanding of the current guidelines. This retrospective study aimed to evaluate whether pharmacist interviews and interventions with patients taking oral antithrombotic drugs in the pharmaceutical outpatient cardiology clinic had favourable clinical outcomes including decreased bleeding. METHODS: The participants included patients visiting the outpatient clinic of cardiovascular internal medicine at the Kobe University Hospital from January-December 2017, and were taking oral antithrombotic medication. The observation period was from the first visit to the outpatient clinic to October 2021 or death. Patients who received pharmacist intervention more than twice were defined as the pharmacist intervention group. Two control patients per one pharmacist intervention group individual were selected from the non-intervention pool matched for age, gender and antithrombotic medication type. RESULTS: Of the 895 eligible patients, 132 were in the pharmacist intervention group and 264 were selected for the matched non-intervention group. Bleeding events according to the Bleeding Academic Research Consortium criteria over type 2 were significantly lower in the pharmacist intervention group compared with the non-intervention group (17.4% versus 28.4%, P = 0.019). There were no significant differences in mortality and heart failure hospitalisation frequency, stroke, or cardiovascular events between the groups. Multivariate analysis identified age (≥ 65 years) and pharmacist intervention as factors associated with bleeding (odds ratio = 2.29 and 0.51, respectively). CONCLUSION: Pharmacist intervention in the outpatient clinic of cardiovascular internal medicine was effective in reducing the risk of bleeding in patients undergoing antithrombotic therapy.

DOI： 10.1186/s40780-023-00296-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1016/j.dmpk.2023.100529

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記述言語：日本語   出版者・発行元：(一社)日本緩和医療薬学会  

神戸大学医学部附属病院では,緩和ケアチーム担当薬剤師がWHO方式がん疼痛治療法の鎮痛薬リストの強オピオイド鎮痛薬が処方された入院患者をモニタリングしている.今回,非がん性疼痛患者への強オピオイド使用に際して,薬剤師が検出した緩和薬物療法に関する薬物関連問題(Drug Related Problem,以下DRP)とその転帰について後方視的評価を行った.解析対象患者82名のうち47名(57.3%)にDRPを検出し,うち31名に対して病棟薬剤師を介して介入を行った結果,27名のDRPが解消された.初回モニタリング時に検出し,介入したDRPとしては,ガイドラインからみた不適切使用・禁忌(15件)や,適応のない薬剤の選択(18件)が多かった.緩和ケアチーム薬剤師が非がん性疼痛に対するオピオイド処方患者を一元的にモニタリングすることで,DRPを効率的に検出し,その解消につながる可能性がある.(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Parkinson's Disease (PD) is caused by many factors and endoplasmic reticulum (ER) stress is considered as one of the responsible factors for it. ER stress induces the activation of the ubiquitin-proteasome system to degrade unfolded proteins and suppress cell death. The ubiquitin ligase 3-hydroxy-3-methylglutaryl-coenzyme A reductase degradation 1 (HRD1) and its stabilizing molecule, the suppressor/enhancer lin-12-like (SEL1L), can suppress the ER stress via the ubiquitin-proteasome system, and that HRD1 can also suppress cell death in familial and nonfamilial PD models. These findings indicate that HRD1 and SEL1L might be key proteins for the treatment of PD. Our study aimed to identify the compounds with the effects of upregulating the HRD1 expression and suppressing neuronal cell death in a 6-hydroxydopamine (6-OHDA)-induced cellular PD model. Our screening by the Drug Gene Budger, a drug repositioning tool, identified luteolin as a candidate compound for the desired modulation of the HRD1 expression. Subsequently, we confirmed that low concentrations of luteolin did not show cytotoxicity in SH-SY5Y cells, and used these low concentrations in the subsequent experiments. Next, we demonsrated that luteolin increased HRD1 and SEL1L mRNA levels and protein expressions. Furthermore, luteolin inhibited 6-OHDA-induced cell death and suppressed ER stress response caused by exposure to 6-OHDA. Finally, luteolin did not reppress 6-OHDA-induced cell death when expression of HRD1 or SEL1L was suppressed by RNA interference. These findings suggest that luteolin might be a novel therapeutic agent for PD due to its ability to suppress ER stress through the activation of HRD1 and SEL1L.

DOI： 10.1007/s11064-023-04019-2

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Pharmaceutical Society of Japan  

DOI： 10.1248/bpb.b22-00794

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: Sarcopenia is defined as the loss of skeletal muscle mass and function and is associated with increased mortality. Certain genetic polymorphisms represent risk factors used to assess the incidence of sarcopenia; however, few studies have evaluated the association between genetic polymorphisms and sarcopenia after kidney transplantation (KTx). We examined single-nucleotide polymorphisms (SNPs) in the genes involved in sarcopenia after KTx. METHODS: Sixty-five patients who underwent KTx were enrolled in this study. We used the psoas mass index (PMI; the cross-sectional area of the bilateral psoas muscle/height) as a surrogate marker for assessing the extent of sarcopenia. We determined the PMI before KTx and 1 year after KTx, and we identified 5 SNPs in 5 genes associated with sarcopenia in the general population. Finally, the link between the changes in PMI 1 year after KTx and each SNP was examined. RESULTS: The median PMI before KTx and 1 year after KTx was 7.4 (4.6-13.2) and 7.0 (3.6-13.6), respectively. The PMI decreased in 43 patients (66.2%). The alpha-actinin-3 rs1815739 genotype was associated with changes in PMI; the distribution of CT+TT genotypes in the PMI decrease group was significantly higher than that of the CC genotype (odds ratio, 4.23; 95% CI 0.05-0.97; P = 0.025). Moreover, the T allele frequency was significantly higher in the PMI decrease group than in the PMI increase group (odds ratio, 2.34; 95% CI 0.18-0.950; P = 0.025). CONCLUSION: The alpha-actinin-3 rs1815739 genotype may represent a genetic risk factor for sarcopenia after KTx.

DOI： 10.1016/j.transproceed.2023.03.020

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Osimertinib is a key drug for treating epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). Genetic differences may be associated to adverse events (AEs) induced by osimertinib. This retrospective observational multicenter study evaluated the association of genotypes, including STAT3 -1697C>G, CYP3A5 6986A>G, and ABCG2 421C>A, with the incidence of osimertinib-induced AEs in patients with EGFR mutation-positive NSCLC. PATIENTS AND METHODS: A total of 85 patients treated with osimertinib (Institution A: 33 patients, Institution B: 52 patients) were enrolled in the study. Single nucleotide polymorphisms were determined by real-time PCR, and the incidence of AEs was compared for each genotype. RESULTS: Paronychia incidence was 59% for the CC genotype, 19% for the CG genotype, and 19% for the GG genotype at STAT3 -1697C>G. A genotype-related trend was observed (Cochran-Armitage test, p=0.009). Multivariate analysis showed that the CC genotype at STAT3 -1697C>G and female sex were significant independent factors associated with paronychia [odds ratio (OR)=6.41, 95% confidence interval (CI)=1.94-21.20 and OR=3.40, 95%CI=1.03-11.22, respectively]. The incidence of diarrhea was 53% for the CC genotype, 30% for the AC genotype, and 29% for the AA genotype at ABCG2 421C>A, and a genotype-related trend was observed (p=0.048). However, the CC genotype at ABCG2 421C>A was not a significant independent factor associated with diarrhea in multivariate analysis. No significant associations were detected between other polymorphisms and the incidence of AEs. CONCLUSION: STAT3 -1697C>G may be a novel risk factor for osimertinib-induced paronychia in patients with NSCLC.

DOI： 10.21873/anticanres.16331

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND/AIM: Lenvatinib is a multiple-tyrosine kinase inhibitor used to treat hepatocellular carcinoma (HCC), and its systematic concentration varies according to liver function. The albumin-bilirubin (ALBI) grade is a novel indicator for predicting liver function in patients with hepatic disease. This study aimed to investigate the relationship between ALBI grade and HCC patients' lenvatinib treatment duration. PATIENTS AND METHODS: This is a retrospective cohort study of patients with HCC and Child-Pugh A treated with lenvatinib between April 2018 and December 2019. The baseline liver function was determined using the ALBI grade. The primary outcome was discontinuation owing to adverse events. The risk factors for discontinuation owing to adverse effects were analyzed using logistic regression. RESULTS: This investigation included 48 HCC patients. Patients with ALBI grade 2 had a significantly shorter time of discontinuation due to adverse events than those with grade 1 (p=0.036). However, the time of treatment failure did not differ between the groups. Multiple logistic regression analysis showed that ALBI grade 2 and non-use of antihypertensive drugs were independent factors for discontinuation due to adverse events [odds ratio (OR)=14.1, 95% confidence interval (CI)=1.46-135, p=0.022 and OR=5.48, 95% CI=1.13-23.9, p=0.024, respectively]. CONCLUSION: The ALBI grades may be useful in predicting adverse events caused by lenvatinib in patients with HCC and Child-Pugh A.

DOI： 10.21873/anticanres.16279

PubMed

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

This study aimed to determine the effects of pregnancy and ontogeny on risperidone and paliperidone pharmacokinetics by assessing their serum concentrations in two subjects and constructing a customized physiologically-based pharmacokinetic (PBPK) model. Risperidone and paliperidone serum concentrations were determined in a pregnant woman and her newborn. PBPK models for risperidone and paliperidone in adults, pediatric, and pregnant populations were developed and verified using the Simcyp simulator. These models were then applied to our two subjects, generating their "virtual twins." Effects of pregnancy on both drugs were examined using models with fixed pharmacokinetic parameters. In the neonatal PBPK simulation, 10 different models for estimating the renal function of neonates were evaluated. Risperidone was not detected in the serum of both pregnant woman and her newborn. Maternal and neonatal serum paliperidone concentrations were between 2.05-3.80 and 0.82-1.03 ng/ml, respectively. Developed PBPK models accurately predicted paliperidone's pharmacokinetics, as shown by minimal bias and acceptable precision across populations. The individualized maternal model predicted all observed paliperidone concentrations within the 90% prediction interval. Fixed-parameter simulations showed that CYP2D6 activity largely affects risperidone and paliperidone pharmacokinetics during pregnancy. The Flanders metadata equation showed the lowest absolute bias (mean error: 22.3% ± 6.0%) and the greatest precision (root mean square error: 23.8%) in predicting paliperidone plasma concentration in the neonatal population. Our constructed PBPK model can predict risperidone and paliperidone pharmacokinetics in pregnant and neonatal populations, which could help with precision dosing using the PBPK model-informed approach in special populations.

DOI： 10.1111/cts.13473

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：MDPI AG  

Oral lichen planus (OLP) is a type of chronic and refractory stomatitis characterized by abnormal keratinization, which is often painful. There is no consensus regarding treatment options for OLP, particularly in the presence of pain. The current study protocol focuses on the short-term efficacy and long-term safety of an ibuprofen gargle for pain management in patients with OLP. Patients (n = 24) with painful OLP will be enrolled. During a crossover study period, patients in the ibuprofen–placebo (IP) group will receive an ibuprofen gargle (0.6%) on day 1, a placebo gargle on day 2, and an ibuprofen gargle on days 3–5 at least once daily. Patients in the placebo–ibuprofen (PI) group will receive a placebo gargle on day 1, an ibuprofen gargle on day 2, and an ibuprofen gargle on days 3–5 at least once daily. The primary endpoint of the crossover study period is the change in pain level as measured by a visual analogue scale score from before gargle administration to 5 min after gargle administration on days 1 and 2. The primary endpoint of the long-term extension study is assessment of long-term safety. The results of this study may support existing evidence regarding the effectiveness of ibuprofen rinses in treating OLP.

DOI： 10.3390/mps6010007

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記述言語：日本語   出版者・発行元：(一社)日本病院薬剤師会  

神戸大学医学部附属病院では、2019年8月より抗がん薬調製ロボット(以下、調製ロボット)の日常業務での運用を開始した。そこで、調製ロボット導入前後の評価期間として2019年5～7月および2020年8～10月の各3ヵ月間を設定し、薬剤師のがん薬物療法関連業務を比較した。調製ロボット導入後に抗がん薬調製総件数は有意に増加したが、調製ロボットの調製率は調製総件数の29.2%を占め、薬剤師による抗がん薬調製件数は導入前に比べて導入後に有意に減少した(1,653±51 vs.1,330±20件/月、平均値±標準偏差、p<0.01)。また、薬剤師の対患者業務に関して、初回抗がん薬治療時の治療説明件数は導入前後で35±10件/月から55±5件/月へと有意に増加した(p=0.04)。調製ロボットの導入は、薬剤師による調製件数の減少とそれに伴うマンパワーの対患者業務へのシフトに有用である。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J04451&link_issn=&doc_id=20220606220006&doc_link_id=%2Fdg4hppha%2F2022%2F005806%2F006%2F0627-0632%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2022%2F005806%2F006%2F0627-0632%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Oxford University Press (OUP)  

Abstract

Background

Hand-foot skin reaction (HFSR) induced by multiple tyrosine kinase inhibitors (TKIs) is a serious side effect that can cause treatment interruption or decreased dosing. This study was conducted to evaluate the safety and efficacy of bis-glyceryl ascorbate (Amitose bis(di)-glyceryl ascorbate [DGA])-containing cream (DGA cream) for the prevention of sunitinib-induced HFSR.

Methods

A single-arm, open-label phase I/II study was conducted, targeting patients with metastatic renal cell carcinoma (mRCC) who were receiving sunitinib therapy with a schedule of 2 weeks on/1 week off. The participants applied DGA cream to both palmar and plantar surfaces in combination with a moisturizing agent as standard-of-care prophylaxis during two sunitinib treatment cycles (6 weeks). The primary endpoint in phase I was safety defined as dermatological abnormalities and it was determined in the first five participants. The primary endpoint in phase II was efficacy defined as development of grade 1 or higher HFSR defined by Common Terminology Criteria for Adverse Events within 6 weeks and it was determined on a full analysis set (FAS) defined as the population including all participants who used DGA cream once in the study duration. Efficacy in the per protocol set (PPS) defined as the population excluding seven patients whose study treatment was interrupted was evaluated as a secondary endpoint.

Results

Twenty-four patients were enrolled as a FAS. No dermatological abnormalities occurred in the first 5 patients enrolled in the phase I study. Three patients developed HFSR (grade 1: n = 2, grade 2: n = 1) in the observation period. The HFSR incidence rate was 12.5% (3/24; 95% confidence interval [CI]: 2.7%-32.4%) in the FAS, which was significantly lower than the incidence rate predefined as a threshold of 33.3% by a previous report from our hospital (P = .030). The incidence rate in the 17 patients of the PPS was 17.6% (3/17; 95%CI: 3.8%-43.4%).

Conclusion

DGA cream may be safe and effective in the prophylaxis of HFSR in mRCC patients who receive sunitinib therapy (Trial ID: jRCTs051180051).

DOI： 10.1093/oncolo/oyab067

PubMed

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

We evaluated the association of signal transducer and activator of transcription 3 (STAT3) polymorphisms with the incidence of mammalian target of rapamycin (mTOR) inhibitor-induced interstitial lung disease (ILD) in patients with renal cell carcinoma (RCC). We also used lung-derived cell lines to investigate the mechanisms of this association. Japanese patients with metastatic RCC who were treated with mTOR inhibitors were genotyped for the STAT3 polymorphism, rs4796793 (1697C/G). We evaluated the association of the STAT3 genotype with the incidence of ILD and therapeutic outcome. In the 57 patients included in the primary analysis, the ILD rate within 140 days was significantly higher in patients with the GG genotype compared with those with other genotypes (77.8% vs. 23.1%, odds ratio=11.67, 95% confidential interval=3.0644.46). There were no significant differences in progression-free survival or time-to-treatment failure between the patients with the GG genotype and those with other genotypes. An in vitro study demonstrated that some lung-derived cell lines carrying the GG genotype exhibited an increase in the expression of mesenchymal markers, such as fibronectin, N-cadherin, and vimentin, and decreases in E-cadherin, which is an epithelial marker associated with exposure to everolimus, although STAT3 expression and activity were not related to the genotype. In conclusion, the GG genotype of the STAT3 rs4796793 polymorphism increases the risk of mTOR inhibitor-induced ILD, supporting its use as a predictive marker for RCC.

DOI： 10.3727/096504022X16418911579334

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer Science and Business Media LLC  

Abstract

Background

Potentially inappropriate medications (PIMs) and polypharmacy in older adults lead to increase the risk of adverse drug events. This study aimed to evaluate the effectiveness of pharmacist intervention combining the criteria for detecting PIMs with the deprescribing algorithm on correcting PIMs, reducing the number of medications, and readmissions.

Methods

A prospective observational study was conducted at a Japanese University Hospital enrolling new inpatients aged ≥65 years prescribed ≥1 daily medication. Pharmacists detected PIMs based on the criteria combined the screening tool of older persons’ potentially inappropriate prescriptions criteria version 2 with the screening tool for older persons’ appropriate prescriptions for Japanese, examined changes using the deprescribing algorithm, and suggested changes to the physician. The proportion of patients whose number of medications was reduced at discharge and the rate of readmissions within 30 and 90 days were compared between patients without PIMs (without PIMs group), patients who were not suggested to change PIMs (no suggestions group), and patients who were suggested to change PIMs (suggested group).

Results

The study enrolled 544 patients (median age 75.0 years, 54.4% males, median number of medications 6.0/patient). The number of patients with PIMs was 240 (44.1%), and 304 patients had no PIMs (without PIMs group). Among the patients with PIMs, 125 (52.1%) patients received pharmacist suggestions to change ≥1 PIMs (suggested group), and 115 patients received no suggestions for change (no suggestions group). The total number of PIMs was 432, of which changes were suggested for 189 (43.8%). Of these 189 cases, 172 (91.0%) were changed. The proportion of patients whose number of medications was reduced was significantly higher in the suggested group than in the without PIMs group and the no suggestions group [56.8% (71/125) vs. 26.6% (81/304) and 19.1% (22/115), respectively; P &lt; 0.001 in both comparisons]. There were no significant differences in the rates of readmissions within 30 and 90 days among the three groups.

Conclusions

Pharmacist intervention combining the criteria for detecting PIMs with the deprescribing algorithm was effective for correcting PIMs and may be associated with a reduction in the number of medications.

DOI： 10.1186/s40780-022-00243-0

PubMed

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その他リンク： https://link.springer.com/article/10.1186/s40780-022-00243-0/fulltext.html

記述言語：英語   掲載種別：研究論文（学術雑誌）  

WHAT IS KNOWN AND OBJECTIVE: Sunitinib is used as a first-line therapy for metastatic renal cell carcinoma. The primary aim of this study was to determine the optimal total sunitinib (sunitinib plus N-desethyl sunitinib) trough concentration for the alternative dosing schedule: 2-week-on and 1-week-off schedule (2/1 schedule). METHODS: Patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib, whose total sunitinib concentrations were available, were recruited for this study. Out of 19 patients, 17 whose sunitinib dosage was not changed until the measurement of drug concentration were eligible for the analysis of the relationship between total sunitinib concentration and clinical outcome. Individual pharmacokinetic parameters in 19 patients were estimated via the Bayesian analysis. RESULTS: The onset of severe (grade ≥3) adverse effects among 17 patients during 3 weeks as a first course of sunitinib therapy was observed in 7 (41.2%) patients. The median total sunitinib concentration in patients with severe adverse effects was significantly higher compared with that in patients without severe adverse effects [median: 119 (113-131) vs. 87.8 (77.4-102) ng/mL, p = 0.01]. According to the receiver operating characteristic analysis of the onset of severe adverse effects, the cut-off value of the total sunitinib concentration was 108 ng/mL. Patients with a total sunitinib concentration lower than 108 ng/mL had a longer time to first dose reduction or withdrawal due to adverse effects compared with those with a total sunitinib concentration of 108 ng/mL or higher (p = 0.03). The probability without treatment failure was not significantly different between the two concentration groups. In addition, the estimated sunitinib apparent oral clearance (CL/F) was significantly lower in the severe adverse effects group. Our simulation demonstrated that 0.67-time dose is needed for patients with approximately 90.0 ng/mL of sunitinib concentration on day 7 to maintain the concentration at the same level as the patients with higher CL/F. WHAT IS NEW AND CONCLUSION: Maintaining the total sunitinib trough concentrations of less than 108 ng/mL is safe to avoid the onset of serious adverse effects without increasing the treatment failure in patients with metastatic renal cell carcinoma treated with the 2/1 schedule of sunitinib.

DOI： 10.1111/jcpt.13517

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The gut microbiome influences tumor response to immune checkpoint inhibitors (ICIs). The proton pump inhibitors (PPI) significantly impair diversity of the gut microbiota and can affect the efficacy of ICIs. Therefore, the present study aimed to evaluate the influence of PPI on survival in patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. We conducted a retrospective cohort study of patients with metastatic or unresectable urothelial carcinoma receiving pembrolizumab. The use of PPI was defined as any administration for ≥30 d within 60 d prior and/or 30 d after treatment initiation. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method, and Cox proportional hazards regression analysis was performed to investigate prognostic factors based on patient characteristics. Seventy-nine patients were included in the analysis, and 34 patients (43.0%) received PPI. There were no significant differences in OS and PFS between PPI users and nonusers (median OS: 8.2 months vs. 11.2 months, hazard ratio (HR): 1.36, 95% confidence interval (CI): 0.75-2.42, p = 0.296; median PFS: 3.5 months vs. 5.1 months, HR: 1.63, 95% CI: 0.95-2.80, p = 0.069). In the multivariable analysis, PPI use was not associated with OS (HR 0.80, 95% CI 0.40-1.56, p = 0.526) or PFS (HR 1.44, 95% CI 0.79-2.60, p = 0.233). In conclusion, the estimated effect size of PPI use on survival in Japanese patients with metastatic or unresectable urothelial carcinoma treated with pembrolizumab was not reproducible.

DOI： 10.1248/bpb.b21-00939

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Anticancer Research USA Inc.  

BACKGROUND/AIM: Resistance to venetoclax, a selective inhibitor of BCL2 apoptosis regulator (BCL2), is regarded as a clinical problem. However, it is unclear whether resistance to venetoclax induces cross-resistance to other drugs. MATERIALS AND METHODS: Venetoclax-resistant HL60/VEN cells were newly established through continuous exposure of human acute promyelocytic leukemia HL60 cells to venetoclax, and drug sensitivity, apoptotic activity, and mRNA expression were compared between HL60 and HL60/VEN cells. RESULTS: HL60/VEN cells displayed approximately 3-fold resistance to venetoclax, maintained their ability to synthesize DNA and had low apoptotic activity. HL60/VEN cells also exhibited diverse sensitivity to cytotoxic drugs, especially resistance to ATP binding cassette subfamily B member 1 (ABCB1) substrates, and up-regulation of ABCB1 mRNA. However, the sensitivity of HL60/VEN cells to venetoclax was not restored by ABCB1 inhibitor. ABCB1-overexpressing cells did not show resistance to venetoclax. CONCLUSION: HL60/VEN cells exhibited up-regulation of ABCB1 in addition to an alteration in apoptotic activity, and cross-resistance to ABCB1 substrates was clarified. However, sensitivity to venetoclax was hardly affected by ABCB1.

DOI： 10.21873/anticanres.15228

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

BACKGROUND: A multicenter investigation of neonate exposure to potentially harmful excipients (PHEs) in neonatal intensive care units (NICUs) in Japan has not been conducted. METHODS: A multicenter nationwide observational study was conducted. Neonate patient demographic data and information on all medicines prescribed and administered during hospitalization on 1 day between November 2019 and March 2021 were extracted from the medical records. Nine PHEs, paraben, polysorbate 80, propylene glycol, benzoates, saccharin sodium, sorbitol, ethanol, benzalkonium chloride, and aspartame, were selected. PHEs were identified from the package insert and the Interview Form. The quantitative daily exposure was calculated if quantitative data were available for each product containing the PHE. RESULTS: Prescription data was collected from 22 NICUs in Japan. In total, 343 neonates received 2360 prescriptions for 426 products containing 228 active pharmaceutical ingredients. PHEs were found in 52 (12.2%) products in 646 (27.4%) prescriptions for 282 (82.2%) neonates. Benzyl alcohol, sodium benzoates, and parabens were the most common PHEs in parenteral, enteral, and topical formulations, respectively. Quantitative analysis showed that 10 (10%), 38 (42.2%), 37 (94.9%), and 9 (39.1%) neonates received doses exceeding the acceptable daily intake of benzyl alcohol, polysorbate 80, propylene glycol, and sorbitol, respectively. However, due to the lack of quantitative information for all enteral and topical products, accurate daily PHE exposure could not be quantified. CONCLUSIONS: Neonates admitted to NICUs in Japan were exposed to PHEs, and several of the most commonly prescribed medicines in daily clinical practice in NICUs contained PHEs. Neonate PHE exposure could be reduced by replacing these medicines with available PHE-free alternatives.

DOI： 10.1186/s40780-021-00208-9

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

OBJECTIVE: It was reported that the administration of tramadol in patients with cancer pain who have a higher interleukin 6 (IL-6) serum level led to insufficient pain relief. Cytokines produced by tumors, including IL-6, are associated with cancer cachexia. However, whether nonresponse to tramadol is related to cancer cachexia is unknown. The purpose of this study was to examine the relationship between tramadol response and cancer cachexia in patients with cancer pain. METHODS: We conducted a retrospective cohort study of patients with cancer who received tramadol treatment for mild to moderate pain from January 2016 to June 2019. Patients who experienced <20% pain reduction based on the numeric rating scale from baseline to day 7 after treatment with tramadol were defined as nonresponders. Univariate and multivariate logistic regression analyses were conducted to examine the relationships between tramadol response and various patient characteristics, including cancer cachexia. RESULTS: Of 115 patients, 79 were included in the analysis. A total of 24 patients experienced cancer cachexia, and 22 patients were nonresponders. In the univariate logistic analysis, cancer cachexia (odds ratio [OR]: 6.04, 95% confidence interval [CI]: 2.06-17.7), higher white blood cell counts (× 103/μL; OR: 1.28, 95% CI: 1.04-1.61), and lower body mass index (OR: 0.79, 95% CI: 0.66-0.96) were significantly associated with nonresponse to tramadol. The multivariate logistic analysis revealed that cancer cachexia (OR: 5.27, 95% CI: 1.75-15.9) was the only significant factor associated with nonresponse to tramadol. CONCLUSIONS: Cancer cachexia in patients with cancer pain can be associated with nonresponse to tramadol.

DOI： 10.1177/1049909120945570

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Hand-foot skin reaction (HFSR) is a common side effect caused by several tyrosine kinase inhibitors, including sunitinib. However, the nature of the cornifying factors related to the molecular biological mechanisms underlying HFSR remains poorly understood. We used human keratinocyte models to investigate the key cornifying factors for dermatological and biological abnormalities induced by sunitinib. On the basis of the results of microarray analysis using the three-dimensional (3D) human epidermal model, keratin (KRT)6A, serine protease inhibitor (SERPIN)B1, KRT5, and SERPIN Kazal-type 6 were selected as candidate genes related to HFSR. Sunitinib treatment significantly decreased the expression of SERPINB1 and KRT6A in the immunohistochemical staining of the 3D epidermal model. In PSVK1 cells, but not in normal human epidermal keratinocyte cells, both of which are human normal keratinocyte cell lines, sunitinib decreased the expression of KRT6A with a concomitant decrease in levels of phosphorylated extracellular signal-regulated kinases (ERK)1/2 and phosphorylated p38 mitogen-activated protein kinase (MAPK). Inhibitors of the ERK and p38 MAPK signal pathways also significantly decreased KRT6A expression. Sunitinib-induced decrease in KRT6A expression was suppressed by the inhibition of glycogen synthase kinase-3β by enhancing ERK1/2 and p38 MAPK phosphorylation. Thus, sunitinib reduces the expression of KRT6A and SERPINB1 by inhibiting the ERK1/2 and p38 MAPK signalling pathways in the skin model. These changes in expression contribute to the pathology of HFSR.

DOI： 10.1111/exd.14230

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Endoplasmic reticulum (ER) stress has been reported as a cause of Parkinson's disease (PD). We have previously reported that the ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and its stabilizing factor suppressor/enhancer lin-12-like (SEL1L) participate in the ER stress. In addition, we recently demonstrated that neuronal cell death is enhanced in the cellular PD model when SEL1L expression is suppressed compared with cell death when HRD1 expression is suppressed. This finding suggests that SEL1L is a critical key molecule in the strategy for PD therapy. Thus, investigation into whether microRNAs (miRNAs) regulate SEL1L expression in neurons should be interesting because relationships between miRNAs and the development of neurological diseases such as PD have been reported in recent years. In this study, using miRNA databases and previous reports, we searched for miRNAs that could regulate SEL1L expression and examined the effects of this regulation on cell death in PD models created by 6-hydroxydopamine (6-OHDA). Five miRNAs were identified as candidate miRNAs that could modulate SEL1L expression. Next, SH-SY5Y cells were exposed to 6-OHDA, following which miR-101 expression was found to be inversely correlated with SEL1L expression. Therefore, we selected miR-101 as a candidate miRNA for SEL1L modulation. We confirmed that miR-101 directly targets the SEL1L 3' untranslated region, and an miR-101 mimic suppressed the 6-OHDA-induced increase in SEL1L expression and enhanced cell death. Furthermore, an miR-101 inhibitor suppressed this response. These results suggest that miR-101 regulates SEL1L expression and may serve as a new target for PD therapy.

DOI： 10.3389/fnmol.2021.748026

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本医療薬学会  

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.

DOI： 10.1016/j.dmpk.2020.05.006

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本臨床衛生検査技師会  

ミコフェノール酸モフェチル(mycophenolate mofetil;MMF)は臓器移植において主に用いられている免疫抑制薬で、ミコフェノール酸(mycophenolic acid;MPA)のプロドラッグである。MPAのAUC0-12が臨床効果や拒絶反応に相関することから、薬物血中濃度モニタリング(therapeutic drug monitoring;TDM)が推奨されている。血漿中MPA濃度測定には従来LC-MS/MS法やEMIT法などが用いられていたが、前者は操作が煩雑で多大な時間を要すること、後者は代謝産物との交差反応により偽高値を示す可能性があることが知られている。今回、PETINIA法による血漿中MPA測定試薬の基本性能および各種検体条件による影響について検討するとともに、高濃度領域も含めたLC-MS/MS法との相関性について評価した。PETINIA法によるMPA血中濃度測定は、感度や再現性、特異性において良好な性能を示した。血清分離剤による測定値への影響は認められず、保存安定性は試薬添付文書上の期間内で保たれていた。LC-MS/MS法との相関は良好であるが(y=1.18x-0.09、r=0.980、p<0.01)、15μg/mL以上の高濃度領域ではPETINIA法が高値を示すことが明らかとなった。以上より、PETINIA法による血漿中MPA濃度測定は低濃度領域では臨床的に有用性であるが、高濃度領域においては、解釈に注意が必要であることが示唆された。(著者抄録)

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

Background: Oral mucositis frequently occurs in cancer patients treated with chemotherapy and chemoradiotherapy (CRT). This study examined the safety and efficacy of ibuprofen gargle in healthy volunteers and patients with chemotherapy- and concomitant CRT-induced oral mucositis. Methods: We enrolled healthy volunteers and patients with chemotherapy- and CRT-induced oral mucositis. In cohort I, single and multiple doses of ibuprofen gargle (0.6% or 1.0%) were administered to healthy volunteers on day 1 and days 4-10. In cohort II, multiple doses of ibuprofen gargle (0.6%) were administered to patients with complicated grade 2-3 oral mucositis based on the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. The primary endpoint of cohort I was the treatment-related adverse events (TRAEs) as defined by CTCAE version 4.0. The primary endpoint of cohort II was the change in the visual analogue scale (VAS) pain score from before to 15 min after gargle use on day 3. The incidence and severity of TRAEs were assessed based on the CTCAE version 4.0 and a subjective rating scale completed by healthy volunteers and patients. Results: In cohort I, 9 of 10 healthy volunteers were evaluable for safety. All 9 healthy volunteers reported the TRAE of oral irritation with single or multiple use of the gargle. In cohort II, 10 patients were enrolled and evaluable for safety and 7 of 10 patients were evaluable for efficacy. The mean change in the VAS pain score from before to 15 min after using the gargle on day 3 was - 1.28 (95% confidence interval: - 2.06, - 0.51), and all patients experienced some degree of pain relief (range: - 0.2 to - 2.5). All 10 patients reported the TRAE of oral irritation. No other TRAEs of ibuprofen gargle were observed in the healthy volunteers and patients. Conclusion: Despite oral irritation, the ibuprofen gargle appeared to be safe and effective for the pain related to chemo- or CRT-induced oral mucositis. However, ibuprofen-related oral irritation warrants further formulation improvement. Trial registration: This study was registered with the University Hospital Medical Information Network Clinical Trials Registry (UMIN000014433).

DOI： 10.1186/s40780-020-00168-6

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本医療薬学会  

疑義照会における腎機能以外の電解質等の検査値も含めた処方チェックシステムの有用性について評価した。調査期間は2009年6〜11月の6ヵ月間(検査値印字未実施期間;I群)、2010年6〜11月の6ヵ月間(検査値印字実施期間;II群)、2016年9月〜2017年8月の12ヵ月間(チェックシステム導入期間;III群)とした。検査値を根拠とした疑義照会による処方変更件数は1ヵ月あたりI群が0件(0%)、II群が13.8件(6.6%)、III群が22.7件(8.9%)であり、II群と比べてIII群で有意に増加した。変更となった処方の内訳はII群では腎機能関連が最も多かったが、III群では電解質関連の占める割合が大きく増加した。薬剤別では、III群における腎機能関連の疑義照会のうち、レボフロキサシン、ファモチジン、レボセチリジン、セフカペン等が多かった。

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）  

Sustained benzodiazepine use during pregnancy can induce neonatal abstinence syndrome (NAS). In this study, the association between NAS and plasma alprazolam concentration was examined using the measured neonatal concentrations in the time series as well as simulated plasma concentrations of pregnant woman and neonate by physiologically based pharmacokinetic (PBPK) modeling. A neonate born to a mother taking alprazolam daily throughout pregnancy exhibited symptoms such as apnea and vomiting from 9 h to 4 days after birth. Finnegan score was 7 at birth and decreased to 0 by day 4. Apnea improved by 24 h post-delivery and gastrointestinal symptoms disappeared by day 4. The plasma alprazolam concentration in the neonate was 15.2 ng/mL immediately after birth and gradually decreased over 3 days. Measured neonate and estimated maternal plasma alprazolam concentrations were within the 90% prediction intervals of each concentration by PBPK simulation using "pregnancy" and "pediatrics" population parameters including in Simcyp population-based ADME simulator. In conclusion, NAS symptoms such as apnea and digestive events disappeared in parallel with the decrease of the neonate's plasma alprazolam concentrations. Moreover, PBPK modeling and simulation is a useful methodology for toxicological assessment in special characteristics populations lacking specific experimental data.

DOI： 10.1016/j.dmpk.2019.09.002

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

AIM: This study aimed to evaluate the efficacy of pharmacists' assessment and intervention using the Screening Tool for Older Persons' Appropriate Prescriptions for Japanese (STOPP-J) to detect and correct potentially inappropriate medications (PIM) compared with the Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (STOPP) criteria version 2. METHODS: A prospective observational study was carried out at a medical unit of Cardiovascular Surgery and Cardiovascular Internal Medicine in a Japanese university hospital involving new inpatients aged ≥65 years prescribed one or more daily medication. Pharmacists detected PIM based on STOPP-J and STOPP criteria version 2, and corrected them with physicians. The number of patients with PIM, the content and changes in PIM were compared between both criteria. RESULTS: Overall, 230 patients were included (mean age 75.4 years, 162 men, mean number of medications 8.3). STOPP-J detected significantly more patients with PIM than STOPP criteria version 2 (122 [53%] vs 75 [33%], P < 0.001). The number of PIM based on STOPP-J was 232, the physicians were recommended to change 61 (26%) and 50 (22%) were changed. Meanwhile, the number of PIM based on STOPP criteria version 2 was 133, the physicians were recommended to change 61 (46%) and 54 (41%) were changed. Several medications detected as PIM using STOPP-J were not detected using STOPP criteria version 2. CONCLUSIONS: STOPP-J detected significantly more patients with PIM than STOPP criteria version 2, and pharmacists' assessment and intervention based on STOPP-J were suggested to be effective for detecting and correcting PIM. Geriatr Gerontol Int 2019; 19: 1101-1107.

DOI： 10.1111/ggi.13773

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病院薬剤師会  

胃酸分泌抑制剤の併用により酸化マグネシウム(magnesium oxide:以下、MgO)の効果が減弱することが報告されている。本研究では、オピオイド服用患者における便秘改善に要したMgO投与量に対するプロトンポンプ阻害薬(proton pump inhibitor:以下、PPI)併用の影響について調査した。対象は、神戸大学医学部附属病院緩和ケアチームが介入し、モルヒネまたはオキシコドンを定時内服している患者37名とした。便秘改善に要したMgO投与量は、PPI併用群、非併用群ともに平均約20mg/kg/dayであり、有意差は認められなかった。しかし、65歳未満の患者における便秘改善に要したMgO投与量は、PPI併用群で非併用群と比べて有意に多かった(27.4±10.2mg/kg/day vs 19.2±2.5mg/kg/day、p=0.03)。以上、65歳未満の非高齢患者においてはPPIの併用がMgOの効果減弱に寄与する可能性がある。(著者抄録)

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2019&ichushi_jid=J04451&link_issn=&doc_id=20190805190012&doc_link_id=%2Fdg4hppha%2F2019%2F005508%2F012%2F0964-0968%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2019%2F005508%2F012%2F0964-0968%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：JMIR Publications  

Background: Hand-foot skin reaction (HFSR) is a serious side effect induced by multiple-tyrosine kinase inhibitors (TKIs). HFSR can cause treatment interruption or decreased dosing. HFSR also markedly decreases quality of life and is associated with the therapeutic efficacy of multiple-TKIs. Therefore, the management and prevention of HFSR is an important issue; however, an effective method for its prevention has not been established. Specific ascorbic acid derivatives can reverse multiple-TKI-induced keratinocyte growth and pathological changes in vitro. Objective: This study was designed to evaluate the safety of bis-glyceryl ascorbate (Amitose DGA), a novel, hydrosoluble, and moisturizing ascorbic acid derivative, in patients with renal cell carcinoma (RCC) receiving sunitinib therapy. This study was also designed to evaluate Amitose DGA's preventive efficacy for sunitinib-induced HFSR. Methods: This is a Phase I/II, single-center, uncontrolled, single-arm, open-label trial. We will recruit a total of 30 patients with RCC receiving sunitinib therapy, with a 2-week-on and 1-week-off schedule. The participants will apply Amitose DGA-containing cream over both palmar and plantar surfaces within two treatment cycles (ie, 6 weeks) of sunitinib in combination with a general moisturizing agent, in addition to standard-of-care processes. Safety assessments will include dermatological abnormalities, clinical laboratory tests, and incidence of adverse events. Efficacy assessments will include development of HFSR and therapeutic outcomes associated with sunitinib. Results: Recruitment to the study began in August 2017 and is ongoing in Japan. To date, 21 subjects have been recruited. Study completion is expected in 2021. Conclusions: This is the first clinical study of Amitose DGA-containing cream in patients with RCC who are receiving sunitinib therapy. The single-center, single-arm, open-label design was selected to maximize subject exposure and increase the likelihood of achieving our study endpoints. The results will provide valuable and preliminary evidence of the effects of Amitose DGA-containing cream on HFSR.

DOI： 10.2196/14636

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

The purpose of the study was to evaluate the ability of different beverages to mask the bitterness of zopiclone and eszopiclone in tablet formulations using the artificial taste sensor and human gustatory sensation testing. The beverages tested for bitterness-masking effects were: Mugicha, Sports beverage, Lactic acid drink, Orange juice and a diluted simple syrup (an 8.5% sucrose solution). The bitterness intensities estimated by the taste sensor of zopiclone or eszopiclone one-tablet solutions mixed with the various beverages, corresponded well with the observed bitterness intensities measured by gustatory sensation testing. The Sports beverage, Lactic acid drink and Orange juice significantly suppressed the bitterness intensity of both zopiclone and eszopiclone 1-tablet solutions compared with water when tested in the artificial taste sensor. Sports beverage, Lactic acid drink and Orange juice all contain citric acid as acidifier, so it was postulated that citric acid was involved in the mechanism of bitterness intensity suppression of zopiclone and eszopiclone 1-tablet solutions by these three beverages. It was then shown that citric acid suppressed the bitterness intensity of a zopiclone one-tablet sample solution in a dose-dependent manner. 1H-NMR spectroscopic analysis of mixtures of citric acid with zopiclone suggested that the carboxyl groups of citric acid interact with the amine group on zopiclone. This study therefore showed that the bitterness intensities of zopiclone and eszopiclone can be suppressed by citric-acid-contained beverages and suggests that this bitterness suppression is due to a direct electrostatic interaction between citric acid and the two drugs.

DOI： 10.1248/cpb.c18-00502

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本臨床衛生検査技師会  

mTOR阻害薬であるエベロリムスは、臓器移植における免疫抑制剤として主に用いられている。エベロリムスの投与に関しては、急性拒絶反応に対する有効性、副作用に対する安全性から薬物血中濃度モニタリング(TDM)を定期的に行うことが必要である。全血中のエベロリムス濃度測定には、LC-MS/MS法が用いられていたが、操作が煩雑であるために臨床の日常業務における測定には不適当であった。近年、ラテックス免疫比濁法(LTIA法)を原理とする試薬が開発されたが、推奨トラフ値はLC-MS/MS法の測定値をもとに設定されており、測定法による値の差の評価が必要であると言われている。そこで今回、新たに開発された電気化学発光免疫測定法(ECLIA法)による「エクルーシス試薬エベロリムス」の基礎的検討を行った。ECLIA法による測定は再現性および感度が良好であり、LTIA法による測定値との相関は、y=1.24x+1.48(r=0.854)と良好であった。以上の結果から、ECLIA法はLTIA法による血中エベロリムス濃度の測定と同等以上の感度・精度を有することが確認され、エベロリムスのTDMに有用である可能性が示唆された。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本臨床化学会  

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Springer-Verlag France  

Background: The expression level of signal transducer and activator of transcription 3 (STAT3) in tumor cells is reported to associate with response to therapy and with survival time in various types of cancer. Objective: This retrospective study aimed to elucidate the association of STAT3 expression in tumor cells with the therapeutic outcomes of sunitinib in patients with renal cell carcinoma (RCC). Patients and Methods: Patients with metastatic RCC who received sunitinib therapy were enrolled in this study. All patients underwent nephrectomy for RCC, and nephrectomy specimens were stained for STAT3 and phosphorylated STAT3 (p-STAT3) by immunohistochemistry. Results: We assessed 51 patients receiving sunitinib as a first-line therapy. STAT3 expression levels did not influence progression-free survival (PFS) and overall survival (OS)
however, patients with p-STAT3-positive tumors exhibited significantly worse PFS compared with those with p-STAT3-negative tumors (log-rank test, P = 0.034). OS tended to be prolonged in patients with p-STAT3-negative tumors. Objective response rate or disease control rate based on the best overall response did not show a significant association with STAT3 or p-STAT3 expression. Univariate Cox proportional hazard regression analyses for clinical predictors revealed that p-STAT3 positivity significantly correlated with shorter PFS (hazard ratio [HR], 2.22, P = 0.041), whereas p-STAT3 expression was not related to the OS. Conclusions: Activated STAT3 in tumor tissues shows a significant association with poor prognosis in patients with RCC who received sunitinib as a first-line therapy, and positive p-STAT3 expression could be a potential biomarker for refractoriness to sunitinib therapy. [Figure not available: see fulltext.].

DOI： 10.1007/s11523-018-0563-4

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Elsevier USA  

Background: New-onset diabetes mellitus after transplantation (NODAT) is a risk factor for both cardiovascular disease and poor graft survival after kidney transplantation (KTx). In this study, we identified single-nucleotide polymorphisms (SNPs) in genes involved in glucose metabolism and examined the correlation between these SNPs and glucose intolerance after KTx. Methods: Thirty-eight patients with normal glucose tolerance before KTx were included in this study. Patients with plasma glucose levels of &gt
140 mg/dL at 120 minutes on the 75-g oral glucose tolerance test at 1 year after KTx were classified as having new-onset impaired glucose tolerance (NIGT). We identified 8 SNPs in 7 genes that are involved in glucose metabolism among the patients included in this study, and compared the prevalence rate of NIGT among SNPs in each gene. Results: Of the 38 patients, 11 (28.9%) were diagnosed with NIGT. For rs4982856 in the PCK2 gene, the distribution of genotypes among the total patient population was as follows: T/T, 12 (31.6%)
T/C, 22 (57.9%)
and C/C, 4 (10.5%). Seven of 11 patients with NIGT had the T/T genotype of rs4982856, whereas only 5 of 27 patients with normal glucose tolerance had this genotype. The T allele frequency of the rs4982856 was significantly higher in the NIGT group than in the normal group (81.8 vs 52.8%, respectively
P =.015). Conclusion: Our study indicates that the T allele of the rs4982856 SNP in the PCK2 gene may be a risk factor for glucose intolerance after KTx.

DOI： 10.1016/j.transproceed.2018.01.042

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本医療薬学会  

薬剤師歴が1〜8年目の薬剤師29名を対象とした。参加者を2群に分け、チーム基盤型学習(TBL)群と講義群に割り当てた。ジャーナルクラブの実施前に行ったプレテストのスコアと薬剤師歴、ジャーナルクラブに参加する前のモチベーションは、講義群とTBL群で有意差は認めなかった。ジャーナルクラブ参加前の予習時間は、TBL群において有意に短かった。主要評価項目であるプレテストとジャーナルクラブ直後のポストテストのスコア差は、講義群とTBL群で有意差は認めなかったが、プレテストのスコアで調整したプレテストとジャーナルクラブ直後のポストテストのスコア差は、TBL群で有意に高かった。ジャーナルクラブ直後のポストテストのスコアはTBL群で有意に高かった。ジャーナルクラブ1ヵ月後のポストテストのスコアは講義群とTBL群で有意差は認めないものの、TBL群においてスコアは高い傾向にあった。アンケートの結果、ジャーナルクラブに対する満足度は講義群とTBL群で有意差は認めなかった。TBLについてジャーナルクラブの満足度に対する顧客満足度分析を行い、重要維持項目は、「司会者の熱意」および「論文内容の解説」であった。

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その他リンク： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J03520&link_issn=&doc_id=20180525340005&doc_link_id=%2Fdb5pharm%2F2018%2F004405%2F005%2F0236-0243%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdb5pharm%2F2018%2F004405%2F005%2F0236-0243%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：Humana Press Inc.  

The prognosis of patients with metastatic renal cell carcinoma has drastically improved due to the development of molecular-targeted drugs and their use in clinical practice. However, these drugs cause some diverse adverse reactions in patients and sometimes affect clinical outcomes of cancer therapy. Therefore, predictive markers are necessary to avoid severe adverse reactions, to establish novel and effective prevention methods, and to improve treatment outcomes. Some genetic factors involved in these adverse reactions have been reported
however, perspectives on each adverse response have not been integrated yet. In this review, genetic polymorphisms relating to molecular-targeted therapy-induced adverse reactions in patients with renal cell carcinoma are summarized in the points of pharmacokinetic and pharmacodynamic mechanisms. We also discuss about the relationship between systemic drug exposure and adverse drug reactions.

DOI： 10.1007/s12032-017-1077-0

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記述言語：英語   掲載種別：研究論文（学術雑誌）  

DOI： 10.1186/s40780-018-0126-y

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PHARMACEUTICAL SOC JAPAN  

Hand foot skin reaction is recognized as one of the most common adverse events related to multiple tyrosine kinase inhibitors, but an effective prevention method has not been identified. The chief aim of this study was to find a mechanism-based preventive method for the skin toxicity induced by sorafenib using vitamin C derivatives. The effects of ascorbyl-2-phosphate magnesium (P-VC-Mg) on the molecular and pathological changes induced by sorafenib were investigated in human keratinocyte HaCaT cells. The cell growth inhibition and apoptotic effects of sorafenib were attenuated by P-VC-Mg. Moreover, P-VC-Mg inhibited the decrease of signal transducer and activator of transcription 3 (STAT3) phosphorylation and the expression of apoptosis suppressors treated by sorafenib. HaCaT cells transfected with the STAT3 dominant-negative form (STAT3DN) and STAT3 small interfering RNA (siRNA) combined with P-VC-Mg did not exhibit the attenuation of cell growth inhibition. Interestingly, after exposure to sorafenib in a three dimensional (3D) skin model assay, the basal layer was significantly thickened and the granular and spinous layers became thinner. In contrast, after exposure to sorafenib with P-VC-Mg, the thickness of the basal, granular, and spinous layers was similar to that of the control image. These findings suggest that P-VC-Mg attenuates sorafenibinduced apoptosis and pathological changes in human keratinocyte cells and in the 3D skin model mediated by the maintenance of STAT3 activity.

DOI： 10.1248/bpb.b17-00386

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：神戸大学医学部  

Albumin-bound paclitaxel (Abraxane®, nab-paclitaxel) is not recommended to be administered concurrently or sequentially with other drugs due to concern for instability. The need to administer drugs separately increases infusion time. We evaluated the comp

DOI： 10.24546/81009873

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本医薬品情報学会  

調査対象医薬品を、2016年4月現在の院内採用医薬品(採用医薬品)とし、本邦の相互作用情報について、添付文書の使用禁忌(原則禁忌も含む)、併用禁忌を調査対象項目として、MD bank(MB)を用い、MBおよびUp to Date(UD)における医薬品相互情報を収集し、一方ではあり、他方ではなしの組合せはないか比べ見出された課題を解消するツールとして、MBとUDの相互作用を迅速に検索できるシステムを構築し、情報収集と整合性の検討を行った。2016年4月現在の採用医薬品は内服薬739品目、外用薬254品目、注射薬637品目の合計1630品目であった。医薬品名検索で検索できなかった品目が305、うち採用医薬品と同一剤形の医薬品が検索できなかった品目が8あった。採用医薬品同士の医薬品相互作用の組合せ2655270通り中、MB、UDで相互作用の情報が収集できたのは329586組、MBでは使用禁忌と併用注意あわせて241270組の相互作用の情報収集ができた。

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PHARMACEUTICAL SOC JAPAN  

Signal transducer and activator of transcription (STAT) 3 is a key factor in homeostasis of the oral mucosa by regulating the production of inflammatory cytokines. Sunitinib is a substrate of P-glycoprotein (multidrug resistance (MDR)-1/ABCB1) and breast-cancer resistance protein (BCRP/ABCG2). In this retrospective study, we evaluated the association between sunitinib-induced stomatitis and STAT3, ABCB1, and ABCG2 polymorphisms in patients with metastatic renal cell carcinoma (mRCC). Fifty-two Japanese patients with RCC treated with sunitinib were retrospectively genotyped to elucidate a potential association between STAT3, ABCB1, and ABCG2 polymorphisms and stomatitis development. Stomatitis occurred in 22 out of 52 patients. The TT+TC genotypes at STAT3 rs744166 had an odds ratio of 5.00 against CC genotype for the stomatitis development (95% confident interval, 0.97-25.8). In the Kaplan-Meier method for the cumulative incidence of stomatitis, a statistically significant difference was observed between the TT+TC and CC genotypes in STAT3 rs744166 (p=0.037). Both multiple logistic regression analysis and Cox proportional-hazards regression analysis show STAT3 rs744166 TT+TC genotypes and serum creatinine in each patient were significant independent factors for stomatitis development. In conclusion, STAT3 polymorphism may be a novel risk factor for sunitinib-induced stomatitis in patients with mRCC.

DOI： 10.1248/bpb.b16-00875

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ACADEMIC PRESS INC ELSEVIER SCIENCE  

Hand-foot skin reaction (HFSR) is a common side effect of multiple tyrosine kinase inhibitors (mTKIs). HFSR can necessitate dose reductions or interruption of therapy owing to its negative effect on the quality of life. Therefore, effective use of mTKIs requires measures to prevent HFSR. We evaluated the effect of prostaglandin El (PGE(1)) on HFSR, because PGE(1) is already used to treat bed sores and skin ulcers and has established angiogenic and antiproliferative effects in keratinocytes. We found that the patho-genesis of sorafenib-induced HFSR is characterized by a decrease in levels of a phosphorylated signal transducer and activator of transcription 3 (STAT3). We investigated the effect of PGE(1) on the sorafenib-mediated reduction in phosphorylated STAT3 levels in HaCaT human epidermal keratinocytes. In cells treated with sorafenib, phosphorylated STAT3 levels decreased in a concentration-dependent manner, and this effect was blocked in cells treated with sorafenib and PGE(1). Furthermore, the expression of phosphorylated STAT3, the antiapoptotic proteins myeloid cell leukemia-1 (Mcl-1) and survivin decreased in cells pretreated with an inhibitor of CAMP response element binding protein (CREB). Cell viability increased in cells treated with sorafenib and PGE(1) compared with that in cells treated with sorafenib alone, and these effects were not observed in STAT3 knockdown HaCaT cells. Collectively, these findings indicate that PGE1 blocks the inhibitory effects of sorafenib on cell growth by maintaining the activity of STAT3 and enhancing the CREB activity. Therefore, PGE(1) might represent an effective treatment for the prevention of sorafenib-induced HFSR. (C) 2017 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2017.02.107

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY  

What is known and objectivesThe Screening Tool of Older Persons' Potentially Inappropriate Prescriptions (stopp) criteria were updated in 2014 (stopp criteria ver.2), but few studies have evaluated the usefulness of stopp criteria in elderly patients. This prospective observational study evaluated the prevalence of potentially inappropriate medications (PIMs), and the efficacy of hospital pharmacists' assessment and intervention based on stopp criteria ver.2.
MethodsThe study was conducted at three medical units of Kobe University Hospital between April 2015 and March 2016. Pharmacists assessed and detected PIMs based on stopp criteria ver.2 and considered the patient's intention to change the prescription at the time of admission of each patient. If the pharmacists judged that benefits outweighed risks of prescription change and the patients consented to change the medications, they recommended the doctor to change the prescription. If there was a risk of exacerbation of disease by the change of medications and the pharmacists judged it to be difficult to adjust medications during hospitalization or the patients did not consent to change the medications, they did not recommend to change it. The pharmacists and the doctors discussed and finally decided whether to change the PIMs or not. The number of patients prescribed PIMs, the number and contents of PIMs, and the number of medications changed after pharmacists' intervention were calculated.
ResultsTotally, 822 new inpatients aged &gt;= 65 years prescribed &gt;= 1 daily medicine were included. Their median (interquartile range) age was 75.0 (71.0-80.0) years, and 54.9% were male. According to the criteria, 346 patients (42.1%) were prescribed &gt;= 1 PIMs. Patients prescribed PIMs took significantly more medications than others: 10.0 (7.0-13.0) vs. 60 (4.0-9.0), P &lt; 0001. The total number of PIMs was 651%, 47.6% of which (n = 310) were recommended the doctors to change, and 292 of 651 PIMs (44.9%) were finally discontinued/changed after pharmacists' assessment and intervention. PIMs related to benzodiazepines, including Z-drugs, were most frequent, with a detailed classifications as follows (changed/total): (i) benzodiazepines for 4 or more weeks (75/205), (ii) drugs that predictably increase the risk of falls in older people (benzodiazepines) (30/67) and (iii) drugs that predictably increase the risk of falls in older people (hypnotic Z-drugs) (15/31).
ConclusionOver 40% elderly patients were prescribed PIMs, and pharmacists' assessments and interventions based on stopp criteria ver.2 were useful in detecting and correcting prescription of PIMs.

DOI： 10.1111/jcpt.12496

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本医療薬学会  

「薬剤師外来」は、総合内科外来担当医1名と心臓血管外科外来担当医1名を対象に行い、薬剤師歴12年の薬剤師1名が専任で担当した。総合内科外来または心臓血管外科外来の「薬剤師外来」を受診した全ての患者を対象とした。「薬剤師外来」を受診した群(介入群)と比較するため、「薬剤師外来」を担当している医師と経験歴や専門領域が同様の総合内科医および心臓血管外科医各1名の外来を同一期間に受診した患者を非介入群とした。介入群は延べ517名であり、うち総合内科が338名、心臓血管外科が179名であった。介入群全体での中止および減量に関する処方変更件数および変更率は93件(18.0%)で、うち中止が64件(12.4%)、減量が29件(5.6%)であった。非介入群では、中止および減量が76件(10.1%)、うち中止が57件(7.6%)、減量が19件(2.5%)で、処方変更率はいずれも介入群が非介入群と比較して有意に高かった。介入群で中止・減量した薬剤に起因すると思われる症状の再発・再燃を5件認め、消化性潰瘍治療薬で3件、抗アレルギー薬で2件であった。非介入群では中止・減量に伴う有害事象の発現が6件あった。

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病院薬剤師会  

超短時間型睡眠薬であるエスゾピクロン錠は、催眠活性の大部分を有するS体を抽出して開発されているため、ラセミ体であるゾピクロン錠に比べてより低用量で同等の催眠作用を有すると報告されている。一方、副作用である苦味について直接比較した検討は少ないが、承認時の臨床試験結果を比較した場合、ゾピクロン錠に比べてエスゾピクロン錠で報告が多いことが認められる。我々は前報で、錠剤を溶解した試験液ではゾピクロンがより強い苦味を有することを示したが、本研究では、内服後の評価を行うことを目的としてランダム化二重盲検クロスオーバー試験を実施した。その結果、ゾピクロン錠を内服した翌日でより強い苦味強度を示すとともに苦味が長く持続することが示された。この結果は、添付文書やインタビューフォームなどとは異なる結果となったが、医師や薬剤師が薬剤の選択や情報提供を行ううえで、より適切な根拠となる知見が得られたものと考える。(著者抄録)

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本病院薬剤師会  

現代の日本人における不眠症の有病率は、成人で約20%と言われている。睡眠治療にはベンゾジアゼピン系睡眠薬が主に使用されているが、より依存性が低い非ベンゾジアゼピン系睡眠薬として、ゾピクロン錠やエスゾピクロン錠が広く使用されている。両剤はともに味覚異常を示すことで知られているが、エスゾピクロン錠は、ラセミ体であるゾピクロンから、活性を有するS体のみを精製して開発されており、明確な違いは明らかではない。そこで本研究では、両剤の苦味を比較することを目的に検討を行った。その結果、苦味特異的な物質に反応を示す味覚センサ試験で、ゾピクロン錠がより強い苦味を示した。さらに健康成人を対象としたヒト官能試験でも、ゾピクロン錠でより強い苦味を示すことが認められた。本検討は薬剤の苦味強度を示すものであるが、エスゾピクロン錠に比べてゾピクロン錠がより強い苦味強度を有する可能性が示唆された。(著者抄録)

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：HUMANA PRESS INC  

Signal transducer and activator of transcription (STAT) 3 is a key factor in multiple tyrosine kinase inhibitor (mTKI)-induced growth inhibition and apoptosis of renal cell carcinoma (RCC) cells. This study aimed to identify associations between single-nucleotide polymorphisms (SNPs) in the STAT3 gene and tumor response to mTKIs in patients with metastatic RCC (mRCC). Seventy-one patients with clear cell RCC treated with any mTKI were retrospectively genotyped to elucidate a potential association between STAT3 SNPs and overall best response to drugs. Of 50 patients included for analysis, a partial or complete response was observed in 17. A significant association was found between rs4796793 alleles and tumor response [G vs. C, odds ratio (OR) 3.25, 95 % confidence interval (CI) 1.30-8.07]. There were a higher percentage of responders with the C/C genotype at rs4796793 than with the G/C + G/G genotypes (OR 4.46, 95 % CI 1.31-15.28). Time-to-event analysis demonstrated a statistically significant difference between patients with the CC genotype and those with G/C + G/G genotypes in time-to-treatment response, but not in progression-free survival or time-to-treatment failure. The rs4796793 genotype is a novel predictive factor of the response to mTKIs in patients with mRCC. However, prospective translational trials with larger patient cohorts are required to confirm these results.

DOI： 10.1007/s12032-016-0733-0

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(一社)日本医療薬学会  

STOPP Criteriaを用いた高齢者のポリファーマシーに対する薬剤師による介入について検討した。1剤以上使用中の薬剤がある65歳以上の新規入院患者201例(男性173名、女性128名、74.8±6.2歳)を対象とした。入院時持参薬の確認時に、STOPP Criteriaを用いて薬剤師が潜在的に不適切な処方(PIM)のスクリーニングを行った。STOPP Criteriaに該当した患者は81例で、非該当患者に比べ有意に服用薬剤数が多かった。STOPP Criteria該当患者では非該当患者に比べ有意に女性の割合が高く、年齢が高かった。服用薬剤数が多い患者群ほどSTOPP Criteria該当割合も増加する傾向が見られた。該当項目としてはNSAID、カルシウムチャネル拮抗薬、ベンゾジアゼピン系薬、βブロッカーに関連する項目が多く、これらの合計で全体の75%以上を占めた。STOPP Criteriaの65項目の内、該当のあった項目は23項目で全体の35.3%であった。該当したPIMは合計125件で、その内変更件数は35件であった。また積極的推奨件数は61件で、その内変更件数は32件であった。

DOI： 10.5649/jjphcs.42.78

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPRINGER  

Signal transducer and activator of transcription (STAT)3 is a reported mediator of molecular-targeted drug-induced keratinocyte toxicity.
Our purpose was to assess the association of single nucleotide polymorphisms (SNPs) in STAT3 with hand-foot skin reactions (HFSR) in patients with metastatic renal cell carcinoma (mRCC) treated with multiple tyrosine kinase inhibitors (mTKIs).
Sixty-five Japanese patients with clear cell renal cell carcinoma who were treated with any mTKI at Kobe University Hospital were retrospectively genotyped to elucidate a potential association between STAT3 polymorphisms and HFSR development.
The final analysis included 60 patients. HFSR was observed in 46 patients. The GG, GC, and CC genotypes at rs4796793 were found in 9, 27, and 24 patients, respectively. Three other STAT3 polymorphisms exhibited tight linkage disequilibrium with rs4796793. A significant association was found between the rs4796793 allele and HFSR [G vs. C; odds ratio [OR], 4.33; 95 % confidence interval [CI], 1.80-10.45; P = 0.001]. The GG genotype had the highest OR compared with GC + CC genotypes (OR, 10.75; 95 % CI, 2.38-48.07; P = 0.001). In a time-to-event Kaplan-Meier analysis, a statistically significant difference was observed between the GC + CC and the GG genotypes (P = 0.009).
The rs4796793 genotype appears to be a novel factor for mTKI-induced HFSR in patients with mRCC. Prospective translational trials with larger numbers of patients are required to confirm our results. This research suggests a potential benefit of STAT3 polymorphism screening in patients treated with mTKIs

DOI： 10.1007/s11523-015-0382-9

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：AMER SOC PHARMACOLOGY EXPERIMENTAL THERAPEUTICS  

Sunitinib is widely used for treating renal cell carcinoma (RCC). However, some patients do not respond to treatment with this drug. We aimed to study the association between sunitinib sensitivity and epithelial-mesenchymal transition (EMT) regulation via epidermal growth factor receptor (EGFR) signaling, which is a mechanism of resistance to anticancer drugs. Three RCC cell lines (786-O, ACHN, and Caki-1) were used, and then we evaluated cell viability, EMT regulatory proteins, and signal transduction with sunitinib treatment. Cell viability of 786-O cells was maintained after treatment with sunitinib. After treatment with sunitinib, EGFR phosphorylation increased in 786-O cells, resulting in an increase in the phosphorylation of extracellular signal-regulated kinase, nuclear translocation of beta-catenin, and expression of mesenchymal markers. These results suggest that sunitinib induced EMT via activation of EGFR in 786-O cells, but not in ACHN and Caki-1 cells. Caki-1/SN cells, a resistant cell line generated by continuous exposure to sunitinib, displayed increased phosphorylation of EGFR. Cell viability in the presence of sunitinib was decreased by erlotinib, as the selective inhibitor of EGFR, treatment in 786-O and Caki-1/SN cells. Similarly, erlotinib suppressed sunitinib-induced EGFR activation and upregulated mesenchymal markers. Thus, we postulate that resistance to sunitinib in RCC may be associated with EMT caused by activation of EGFR.

DOI： 10.1124/jpet.115.226639

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担当区分：責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Cordyceps militaris (CM) is gaining attention as a traditional medicinal food, but its molecular biological mechanisms for anti-cancer activity are not identified or clarified. We aimed to elucidate the synthesizing apoptotic effects of CM extracts and to determine the biological effects of CM extract against cordycepin alone in a renal cell carcinoma (RCC) cell line. CM extract showed higher effects of growth inhibition, apoptotic effect, and cell cycle arrest than cordycepin alone. Moreover, CM extract activated extracellular signal-regulated kinase (Erk) highly more than cordycepin alone. We suggest that cordycepin and CM extract induced apoptosis via the activation of Erk dominantly and AMP-activated protein kinase slightly; CM extract has more potent effects on apoptotic effects associated with Erk activation than cordycepin alone. Copyright (c) 2015 John Wiley & Sons, Ltd.

DOI： 10.1002/ptr.5305

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担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：PUBLIC LIBRARY SCIENCE  

Hand-foot skin reaction is a most common multi-kinase inhibitor-related adverse event. This study aimed to examine whether the toxicity of sorafenib and sunitinib for human keratinocytes was associated with inhibiting signal transduction and activator of transcription 3 (STAT3). We studied whether STAT3 activity affects sorafenib-and sunitinib-induced cell growth inhibition in HaCaT cells by WST-8 assay. Stattic enhanced the cell-growth inhibitory and apoptotic effects of sorafenib and sunitinib. HaCaT cells transfected with constitutively-active STAT3 (STAT3C) were resistant to the sorafenib-and sunitinib-induced cell growth inhibition. STAT3 activity decreased after short-term treatment with sorafenib and sunitinib in a dose-dependent manner and recovered after long-term treatment with sorafenib and sunitinib at low doses. Moreover, the expression of survivin and bcl-2 decreased after treatment with sorafenib and sunitinib was concomitant with variations in STAT3 activity. Sorafenib-induced STAT3 inhibition was mediated by regulation via MAPK pathways in HaCaT cells, while sunitinib-induced STAT3 inhibition was not. Thus, STAT3 activation mediating apoptosis suppressors may be a key factor in sorafenib and sunitinib-induced keratinocyte cytotoxicity.

DOI： 10.1371/journal.pone.0102110

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記述言語：日本語   掲載種別：研究論文（学術雑誌）   出版者・発行元：(公社)日本薬剤師会  

本調査研究では、ジェネリック医薬品(GE品)の使用促進を目的として、先発医薬品またはGE品の選択希望に関する実態調査を行い、患者のGE品変更希望に影響を与える重要因子の探索を試みた。調査では、2012年10月に処方箋を当薬局へ持参した患者全員を対象として、患者背景等の情報を抽出し、解析を行った。その結果、医薬品の処方剤数、ハイリスク薬処方、そして患者自己負担がGE品変更希望に対し影響を及ぼすことが示された。また、これらの患者背景及び因子が、患者のGE品選択希望に影響することを薬剤師が把握し、各患者の特徴や傾向に合わせてGE品の説明を行うことで、より効率的なGE品の使用促進につながると期待する。(著者抄録)

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その他リンク： http://search.jamas.or.jp/link/ui/2014041013

担当区分：筆頭著者,　責任著者   記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：BioMed Central  

DOI： 10.1186/1756-9966-32-83

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：SPANDIDOS PUBL LTD  

The effects of 9 calcium antagonists on ABCG2/ BCRP-mediated resistance and transport were examined in He La and SN-38-resistant He La (HeLa/SN100) cells, over-expressing ABCG2/BCRP. Sensitivity to mitoxantrone, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly reversed by the coexistence of the calcium antagonists, except for diltiazem and verapamil. The accelerated transport activity of Hoechst33342, an ABCG2/BCRP substrate, in HeLa/SN100 cells was significantly decreased by the presence of the calcium antagonists, except for diltiazem, nifedipine or verapamil, returning to the level of He La cells. The present study classifies the calcium antagonists into 3 categories: strong (benidipine, felodipine, nicardipine, nisoldipine and nitrendipine), moderate (amlodipine and nifedipine) and weak (diltiazem and verapamil) inhibitors of ABCG2/BCRP.

DOI： 10.3892/mmr.2011.734

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：2  

DOI： 10.1371/journal.pone.0030697

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER SCIENCE BV  

Aim: Combination chemotherapy for treating cancer often is superior in clinical efficacy to monotherapy. The aim of this study was to investigate the schedule-dependent effect of 5-fluorouracil (5-FU) and platinum derivatives (cisplatin or oxaliplatin) in colorectal cancer (CRC) cell lines, and to explore factors affecting it.
Methods: Two human CRC-derived cell lines, DLD-1 and HCT116, were used. Three treatment schedules were tested, and growth inhibitory effects were evaluated with a WST-1 assay. Combined effects were assessed with isobolograms and a combination index. Cellular accumulation and DNA-binding of platinum were measured with inductively coupled plasma mass spectrometry.
Results: Exposure to 5-FU followed by cisplatin produced synergistic effects in DLD-1 cells, and the amount of platinum bound to DNA was substantially increased as compared with that for other schedules. 5-FU and oxaliplatin also tended to be synergistic when 5-FU was given first, but no significant change in the cellular kinetics of platinum was observed. On the other hand, in HCT116 cells, the combined effects of 5-FU and platinum derivatives were comparable among the three schedules.
Conclusion: Exposure to 5-FU followed by cisplatin had a synergistic effect in DLD-1 cells, suggesting that the amount of platinum bound to DNA contributes to this result. Also, the effect was dependent on the type of platinum derivative and cell. (C) 2011 Elsevier B.V. All rights reserved.

DOI： 10.1016/j.ejps.2011.11.023

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：WILEY-BLACKWELL  

Aim: Oral intake of nutrients is often compromised in elderly, multimorbid patients, but parenteral nutrition causes intestinal atrophy and impairs intestinal function. To uncover the molecular mechanisms by which amino acids are involved in intestinal atrophy and recovery, we studied whether the rapamycin-sensitive mechanistic target of rapamycin (mTOR) complex 1 (mTORC1) pathway is involved in this process.
Methods: C57BL/6N mice were fed a glucose solution alone, glucose solution with amino acids or normal chow diet for various lengths of time. Intestinal sections were prepared from these mice and the villus height and villus density were quantified. As a readout for the mTORC1 pathway, the phosphorylation of the ribosomal S6 protein (S6) was analyzed by immunostaining and immunoblotting. To confirm the role of the mTORC1 pathway, the inhibitory effect of a specific mTOR inhibitor, rapamycin, was examined.
Results: Inducing fasting in mice fed only glucose caused time-dependent intestinal mucosal atrophy, whereas supplementation with amino acids protected the intestinal mucosa from atrophy. Phosphorylation of S6 decreased in the intestinal mucosa of mice fed only glucose, whereas supplementation with amino acids increased S6 phosphorylation. Importantly, intraperitoneal injection of rapamycin attenuated the protective effect of amino acids on the intestinal mucosa in a pattern consistent with the decrease of S6 phosphorylation.
Conclusions: These results indicate that the mTORC1 pathway plays a crucial role in the in vivo maintenance of the intestinal mucosa by the oral intake of amino acids. Geriatr Gerontol Int 2012; 12: 131-139.

DOI： 10.1111/j.1447-0594.2011.00729.x

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

Lipid nano-emulsions (LNEs) having a mean droplet size of 50 nm were investigated as drug carriers for paclitaxel (TXL) to achieve its satisfactory loadings and to develop a pharmaceutically acceptable alternative to the current formulation, Taxol. TXL was incorporated into the LNEs at 2.0 mg/ml without changes in particle size or drug precipitation. In the cytotoxicity study, TXL-loaded LNEs had cytotoxicity to HeLa cells equivalent to that of TXL alone; the 50% growth inhibitory concentrations (IC50) of TXL-loaded LNEs and TXL alone were 1.53 +/- 0.23 nM and 1.76 0.08 nM, respectively. However, a cellular accumulation study using 1,6-dipheny1-1,3,5-hexatriene (DPH) as a fluorescent probe showed that the accumulation of DPH-loaded LNEs in HeLa cells was remarkably lower than that of DPH alone. These results indicated that LNEs were a useful vehicle for TXL, even though LNEs themselves could not be efficiently accumulated in HeLa cells.

DOI： 10.3109/02652040903515482

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：ELSEVIER IRELAND LTD  

It is important to clarify the molecular characteristics of tumor cells showing multidrug resistance (MDR) and to identify the novel targets or biomarkers for chemotherapy. The aim of this study is to establish resistant HeLa sublines through exposure to SN-38, an active metabolite of irinotecan hydrochloride, and to investigate their molecular changes. HeLa cells were exposed to SN-38 at 1, 10, or 100 nM, and resistant clones were isolated and named HeLa/SN1, HeLa/SN10, and HeLa/SN100, respectively. Their cellular changes were examined based on growth inhibition assays, the function of ABCG2/BCRP, and a RT-PCR analysis of MDR-related protein. The sublines showed a decrease in sensitivity to not only SN-38 but also other chemotherapeutic agents as compared with HeLa cells. mRNA and protein levels of ABCG2/BCRP were increased, and the transport activity of ABCG2/BCRP was enhanced, in the resistant cells. In addition, the expression levels of ABCC1/MRP1, ABCC3/MRP3, and ABCC5/MRP5 were higher than in HeLa cells. The mRNA levels of GGTI encoding a gamma-glutamyl transferase, but not GCS encoding a gamma-glutamyl cysteine synthetase, were also higher. Other factors examined, i.e., topoisomerase, SLCO1B1, and apoptosis-regulating factors, were comparable among the cells. The overexpression of ABCG2/BCRP was involved in the mechanism of resistance in SN-38-tolerant cells, and ABCC1/MRP1, ABCC3/MRP3, ABCC5/MRP5, and GGT1 may also have participated. (c) 2009 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.canlet.2008.12.033

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記述言語：英語   掲載種別：研究論文（学術雑誌）   出版者・発行元：TAYLOR & FRANCIS LTD  

The aim of this study was to examine the effects of 16 kinds of nonsteroidal anti-inflammatory drugs (NSAIDs) on P-glycoprotein/MDR1 in Caco-2 cells as an intestinal epithelial cell model. Cells were treated with NSAIDs for 24 hours, and then, the expression of MDR1 mRNA was evaluated by reverse-transcriptase polymerase chain reaction. The function of MDR1 in cells pretreated with NSAIDs for 48 hours was evaluated by measuring the cellular amount of rhodamine123, which is a substrate of MDR1. The expression of MDR1 mRNA was increased by diclofenac, fenbufen, indomethacin, and nimesulide and the tended to be increased by meloxicam, mepirizole, and sulindac. However, pretreatment for 48 hours with diclofenac, indomethacin, or nimesulide, but not fenbufen, resulted in a significant increase in the amount of rhodamine123 accumulated. Although NSAIDs without effects on the expression of MDR1 mRNA altered the accumulation of rhodamine123 significantly, the efflux of rhodamine123 from cells was unchanged. In conclusion, the expression of MDR1 mRNA in Caco-2 cells was demonstrated to be increased by treatment with some NSAIDs, although the transport function of MDR1 was unchanged. These findings imply that the NSAIDs did not cause the drug interaction via MDR1 induction.

DOI： 10.1080/01480540903130658

Web of Science

PubMed

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J-GLOBAL

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J-GLOBAL

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記述言語：日本語   出版者・発行元：(株)癌と化学療法社  

世界の死因の上位に悪性腫瘍や腎臓病が位置付けられ,それぞれの罹患者数も経年的に上昇している近年において,がんと腎臓病を併存する患者に薬物療法を適用する機会が増加している。がんと腎臓病の併存は,がん患者の腎障害発生と腎臓病患者や腎移植患者のがんの発生が想定されるが,それらの要因は多様であり対応も異なる。がん薬物療法の実施を検討する上で,開始時点の腎機能を適正に評価することや腎機能の低下する要因を明確に把握することは,治療の良好な予後につながる重要な過程である。また,がん患者では筋肉量が減少した患者の割合が高いことから,腎機能を評価する際は血清クレアチニン値に基づく糸球体濾過値の推算が過大評価となるリスクを理解しておく必要があり,実測値や各種推算値の特性を十分に理解した腎機能評価を行うことが重要である。なお,本解説は,日本腎臓学会・日本癌治療学会・日本臨床腫瘍学会・日本腎臓病薬物療法学会編『がん薬物療法時の腎障害診療ガイドライン2022』(ライフサイエンス出版)の第1章から抜粋し加筆したものである。(著者抄録)

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その他リンク： https://search.jamas.or.jp/default/link?pub_year=2022&ichushi_jid=J00296&link_issn=&doc_id=20221118310002&doc_link_id=%2Fab8gtkrc%2F2022%2F004911%2F002%2F1183-1187%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2022%2F004911%2F002%2F1183-1187%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

記述言語：日本語   出版者・発行元：日本腎臓病薬物療法学会  

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記述言語：日本語   出版者・発行元：(株)日本メディカルセンター  

＜文献概要＞慢性腎臓病(CKD)や透析の患者は健常者と比較して便秘を起こしやすいことが知られており,薬物療法もその要因の一つである.CKD・透析患者において頻用されるポリマー型リン吸着薬やカリウム吸着薬は便秘を高頻度に発症させる.また,日本では高齢のCKD・透析患者も増加しており,高齢による潜在的な不適切処方により便秘を生じる可能性も高い.抗コリン作用,ヒスタミンおよびムスカリン受容体拮抗作用を有する薬剤は,便秘を生じる不適切処方の代表例である.本稿では,便秘を起こしやすい薬剤について,CKD・透析患者に投与される可能性が高いものを中心に高齢者への不適切処方例も含めて概説する.

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その他リンク： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2022&ichushi_jid=J01864&link_issn=&doc_id=20220419290009&doc_link_id=20220610100021&url=http%3A%2F%2Fsearch.jamas.or.jp%2Flink%2Fbc%2F20220610100021&type=jamaslink&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F99999_1.gif

記述言語：日本語   出版者・発行元：(株)東京医学社  

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J-GLOBAL

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記述言語：日本語   出版者・発行元：日本腎臓病薬物療法学会  

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記述言語：日本語   出版者・発行元：(株)じほう  

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記述言語：日本語   出版者・発行元：(株)南山堂  

＜Key Points＞◎表在性皮膚真菌症に使用される経口抗真菌薬は、いずれも肝代謝性で透析による除去も受けない。◎これらの薬剤は、原則、腎機能や透析による用量調整は不要であるが、末期腎不全患者においては血中濃度が上昇する報告もある。◎多くのCYPやトランスポーターは末期腎不全患者で発現量・活性が低下し、透析の実施により低下した発現量・活性が回復する。◎CYPの阻害と腎排泄の低下が同時に生じることにより血中濃度が顕著に上昇する併用薬には注意が必要である。◎CYP阻害作用を有する抗真菌薬の開始時は、検査値と合わせて処方全体を総合的に見直さなければならない。(著者抄録)

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記述言語：日本語   出版者・発行元：日本腎臓病薬物療法学会  

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記述言語：日本語   出版者・発行元：(株)診断と治療社  

＜Headline＞1 治療薬物モニタリング(TDM)は血中濃度等の測定によって、今後の薬物治療に有益な判断をもたらす場合に目的を持って行う。2 分布容積とクリアランスに影響する変動因子を考慮しつつ、投与量と投与間隔を決定する。ただし、血中濃度を治療域に入れることのみを目的とせず、治療効果や副作用等のアウトカムを評価することが重要である。3 今後、血中濃度に加えて、治療効果の指標となるバイオマーカーやファーマコゲノミクス情報の活用や、採血量を低減させる技術や高感度な分析技術の利用がTDMの精密化に寄与する。(著者抄録)

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記述言語：日本語   掲載種別：記事・総説・解説・論説等（商業誌、新聞、ウェブメディア）  

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記述言語：日本語   出版者・発行元：(株)ニュー・サイエンス社  

分子標的治療の進展に伴い、間質性肺炎の報告が経年的に増加しているが、その詳細な発症メカニズムは解明されていない。線維化のin vitroモデルとなるEMTに関する研究が盛んに行われているが、近年、代表的因子であるサイトカインに依存しないシグナル伝達因子の活性変動によりEMTが亢進することが明らかとなり、分子標的治療薬に起因する間質性肺炎の発症メカニズムを考える上での重要な知見が得られている。本稿では、分子標的治療薬による間質性肺炎のシグナル伝達因子に起因する発症メカニズムについて概説する。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)医薬ジャーナル社  

薬剤の投与設計における薬剤師の介入は,医薬品の適正使用の推進において非常に重要な職務である。神戸大学医学部附属病院(以下,当院)では,バンコマイシンの血中濃度測定が実施された全例に対し,薬剤部からの介入を行っている。特に初回投与設計については,当院のニーズに合わせた初回投与ノモグラムを過去のデータを基に作成し,業務の標準化を図っている。今後は,バンコマイシンの処方支援プロトコールに基づいた薬物治療管理の運用を目指している。本稿では,バンコマイシン治療における当院での取り組みを紹介し,薬剤師主導のバンコマイシンの治療計画について考えたい。(著者抄録)

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記述言語：日本語   出版者・発行元：(株)じほう  

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記述言語：日本語   出版者・発行元：医薬ジャーナル社  

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記述言語：日本語   出版者・発行元：(一社)日本医療薬学会  

複数のキナーゼを阻害するマルチキナーゼ阻害薬(mTKI)は、手足皮膚反応(HFSR)とも呼ばれる皮膚障害を高頻度に発症することが治療上重要な問題となる。本稿では、mTKIによる皮膚障害の発症メカニズムにおけるsignal transducer and activator of transcription 3(STAT3)の役割と、発症のリスク因子の特定、ならびにメカニズムに基づく予防法の探索について概説した。ヒト表皮角化細胞に対するmTKIの増殖抑制作用は、STAT3の活性阻害を介したアポトーシス抑制因子の発現低下に起因する可能性が考えられる。また、PGE1はSTAT3の活性維持を介して、角化細胞に対するソラフェニブの増殖抑制作用を軽減し、それに伴う病理変化を軽減させることから、HFSRの新規予防薬となる可能性が示されている。

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記述言語：日本語   出版者・発行元：(公財)薬学研究奨励財団  

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記述言語：日本語   出版者・発行元：(株)北隆館  

分子標的治療の進展に伴い、間質性肺炎の報告が経年的に増加しているが、その詳細な発症メカニズムは解明されていない。線維化のin vitroモデルとなるEMTに関する研究が盛んに行われているが、近年、代表的因子であるサイトカインに依存しないシグナル伝達因子の活性変動によりEMTが亢進することが明らかとなり、分子標的治療薬に起因する間質性肺炎の発症メカニズムを考える上での重要な知見が得られている。本稿では、分子標的治療薬による間質性肺炎のシグナル伝達因子に起因する発症メカニズムについて概説する。(著者抄録)

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記述言語：日本語   出版者・発行元：(一社)日本泌尿器科学会総会事務局  

J-GLOBAL

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記述言語：日本語   出版者・発行元：(公財)政策医療振興財団  

癌化学療法に用いられる薬剤のうちメトトレキサートやフルオロウラシルなどの細胞障害性薬剤では副作用として口内炎があり、その発症機構として、薬剤の唾液分泌による口腔内の薬剤曝露により発症することが報告されている。薬物の唾液分泌にはP糖蛋白質が関与していることが報告されており、特にメトトレキサートやフルオロウラシルはP糖蛋白質の良好な基質とされている。P糖蛋白質をコードするMDR1遺伝子は日本人において遺伝子多型の存在が知られており、3435C&gt;Tと2677G&gt;A/Tの変異が薬物の唾液分泌に影響を及ぼすことが報告されている。今回著者等は、MDR1遺伝子多型の解析法と、唾液中メトトレキサート濃度のHPLCによる定量法を確立したので、その詳細を報告した。

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記述言語：日本語   出版者・発行元：日本医療薬学会  

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記述言語：日本語   出版者・発行元：日本医療薬学会  

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記述言語：日本語   出版者・発行元：(公財)政策医療振興財団  

ソラフェニブ、スニチニブ、アキシチニブでの治療経験を有する腎細胞癌患者42例を対象に、分子標的治療薬による皮膚障害発症群(Grade 1以上)と非発症群に分類し、皮膚障害と皮膚の恒常性に関与する因子(Signal Transducer and Activator of Transcription(STAT)3)の遺伝子変異との関連性について検討した。その結果、皮膚障害の非発症群において、STAT3の遺伝子多型についてはG/G(野生型ホモ)の割合が有意に高かった。発症群においてはG/C(ヘテロ)、C/C(変異型ホモ)の割合が有意に高った。また、Grade 2以上の重症群とGrade 1以上の軽症群に分類し、STAT3遺伝子多型の分布を評価したところ、重症例でC/Cの割合が特に高かった。STAT3の発現量を低下させることで、分子標的治療薬の皮膚表皮角化細胞における増殖抑制作用が増強する可能性について、in vitroで検討を行った結果、si-RNAによりSTAT3をノックダウンさせた細胞はソラフェニブ細胞増殖抑制作用が顕著に高いことが示唆された。また、皮膚3次元モデルを用いて分子標的治療薬による細胞障害性、STAT3活性変動、角化亢進作用の評価を免疫染色法により評価したところ、Sorafenibを基底層側から曝露した皮膚3次元モデルは細胞の増殖が停止し、薄層化を認めた。また、角化層が剥離し、有棘層、顆粒層が表皮に剥出した。

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記述言語：日本語   出版者・発行元：(株)日本医学館  

mTOR阻害薬による口内炎発症機構の分子生物学的解明と副作用バイオマーカーについて検討した。ヒト頬粘膜上皮細胞(HO-1-N-1細胞)を用いた。サイトカインの定量はELISA法、蛋白質のリン酸化及び発現変動解析はウエスタンブロット法を用いた。唾液検体はエベロリムス内服中の腎移植患者を対象とした。エベロリムスによるIL-6の分泌亢進は、IL-6分泌を制御するp38と負に制御するErkの両方の活性化に起因する可能性が示唆された。エベロリムス内服中の腎移植患者5例における内服直前の唾液中エベロリムス濃度を測定し、1例のみ検出可能で1.1nMであった。

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記述言語：日本語   出版者・発行元：日本医療薬学会  

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記述言語：日本語   出版者・発行元：日本医療薬学会  

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記述言語：日本語   出版者・発行元：日本医療薬学会  

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記述言語：日本語   出版者・発行元：日本医療薬学会  

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記述言語：日本語   出版者・発行元：医薬ジャーナル社  

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その他リンク： http://search.jamas.or.jp/link/ui/2012368624

記述言語：日本語   出版者・発行元：(株)医薬ジャーナル社  

6年間の薬学教育を経て、2012年4月に「新しい薬剤師」が誕生した。また同時に、薬剤師業務も大きく変わろうとしている。薬剤師への社会からの期待は確実に高まっている。この期待に応えるには、まず社会から求められるニーズとは何か、医療を牽引する薬剤師になるために必要なものは何かを明確にしなければならない。「次世代薬剤師」に期待される薬剤師像を病院薬剤師からの目線から考えてみると、専門薬剤師とジェネラリスト薬剤師、判断→観察→評価ができる薬剤師、臨床研究ができる薬剤師、多様な技能・知識を有する薬剤師、大学と臨床の協調の中に生まれる薬剤師というイメージが浮かび上がる。新しい薬剤師像と、それを育成するための教育について考えていきたい。(著者抄録)

J-GLOBAL

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記述言語：日本語   出版者・発行元：日本医療薬学会  

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記述言語：日本語   出版者・発行元：(公社)日本薬学会  

J-GLOBAL

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開催年月日： 2021年3月14日

記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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開催年月日： 2021年3月14日

記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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開催年月日： 2021年3月14日

記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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開催年月日： 2021年3月14日

記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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開催年月日： 2021年1月30日 - 2021年1月31日

記述言語：日本語   会議種別：ポスター発表  

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開催年月日： 2020年12月14日 - 2020年12月28日

記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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開催年月日： 2020年10月24日 - 2020年11月1日

記述言語：英語   会議種別：ポスター発表  

開催地：WEB開催  

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開催年月日： 2020年10月24日 - 2020年11月1日

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：WEB開催  

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開催年月日： 2020年10月24日 - 2020年11月1日

記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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開催年月日： 2020年10月24日 - 2020年11月1日

記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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開催年月日： 2020年10月24日 - 2020年11月1日

記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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開催年月日： 2020年6月28日 - 2020年7月10日

記述言語：日本語   会議種別：口頭発表（一般）  

開催地：WEB開催  

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開催年月日： 2018年7月

記述言語：日本語  

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開催年月日： 2016年5月

記述言語：日本語  

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開催年月日： 2015年5月

記述言語：英語  

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開催年月日： 2015年

記述言語：日本語  

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記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：ポスター発表  

開催地：WEB開催  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：ポスター発表  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：日本語   会議種別：ポスター発表  

開催地：京都  

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記述言語：日本語   会議種別：口頭発表（一般）  

開催地：大阪  

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記述言語：日本語   会議種別：ポスター発表  

開催地：京都  

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記述言語：日本語   会議種別：ポスター発表  

開催地：京都  

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記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

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記述言語：日本語   会議種別：ポスター発表  

開催地：京都  

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記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

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記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

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記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：徳島  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：神戸  

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記述言語：日本語   会議種別：ポスター発表  

開催地：神戸  

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記述言語：日本語   会議種別：ポスター発表  

開催地：神戸  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：京都  

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記述言語：英語   会議種別：ポスター発表  

開催地：大阪  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：札幌  

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記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：神戸  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：つくば  

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記述言語：英語   会議種別：ポスター発表  

開催地：つくば  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：熊本  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：神戸  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：熊本  

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記述言語：日本語   会議種別：公開講演，セミナー，チュートリアル，講習，講義等  

開催地：神戸  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（公募）  

開催地：福岡  

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記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡  

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記述言語：日本語   会議種別：口頭発表（一般）  

開催地：福岡  

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記述言語：日本語   会議種別：口頭発表（一般）  

開催地：千葉  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：東京  

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記述言語：日本語   会議種別：口頭発表（一般）  

開催地：神戸  

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記述言語：日本語   会議種別：シンポジウム・ワークショップ パネル（指名）  

開催地：大阪  

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記述言語：英語   会議種別：ポスター発表  

開催地：Iguazu  

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記述言語：日本語   会議種別：ポスター発表  

開催地：広島  

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記述言語：日本語   会議種別：ポスター発表  

開催地：広島  

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記述言語：日本語   会議種別：ポスター発表  

開催地：広島  

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記述言語：日本語   会議種別：口頭発表（一般）  

開催地：札幌  

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記述言語：日本語   会議種別：ポスター発表  

開催地：東京  

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会議種別：口頭発表（一般）  

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会議種別：ポスター発表  

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会議種別：ポスター発表  

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会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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会議種別：ポスター発表  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：ポスター発表  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：ポスター発表  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：ポスター発表  

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会議種別：ポスター発表  

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会議種別：口頭発表（一般）  

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記述言語：英語   会議種別：ポスター発表  

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会議種別：ポスター発表  

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会議種別：ポスター発表  

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会議種別：ポスター発表  

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会議種別：ポスター発表  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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会議種別：口頭発表（一般）  

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会議種別：口頭発表（一般）  

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会議種別：ポスター発表  

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会議種別：口頭発表（一般）  

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会議種別：口頭発表（一般）  

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会議種別：口頭発表（一般）  

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会議種別：シンポジウム・ワークショップ パネル（公募）  

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記述言語：英語   会議種別：ポスター発表  

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記述言語：英語   会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：ポスター発表  

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会議種別：ポスター発表  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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会議種別：ポスター発表  

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会議種別：口頭発表（一般）  

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会議種別：シンポジウム・ワークショップ パネル（指名）  

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記述言語：英語   会議種別：ポスター発表  

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受賞区分：国内学会・会議・シンポジウム等の賞 

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